Gaucher Disease: Task 07 - Research SNPs

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Revision as of 22:56, 30 August 2013 by Kalemanovm (talk | contribs) (Mutation map)

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HGMD

HGMD professional was last updated in March 2013. The free public HGMD version provides data from the release of HGMD professional in 2008. The database contains the first example of disease causing or disease associated mutations as well as disease-associated/functional polymorphisms. The informations are taken from literature or reported functional studies. Only non-silent mutations in the coding region are considered. Each mutation is stored once in the database. Additional to the information shown in the second table below, the information about a mutation includes its associated disease phenotype, chromosomal location, gene symbol and the reference of its first literature report. HGMD professional also provides a mutation viewer. The database has access to more than 250 Journals, that are searched by a combination of computerized and manual procedures to find new detected mutations in published articles about germline mutations causing human genetic diseases.


The Glucocerebrosidase has the gene symbol GBA and the accession number NM_001005741.2 . A research on The Human Gene Mutation Database for GBA leads to the results in <xr id="hgmd"/>.

<figtable id="hgmd">

GBA in HGMD
Mutation Type Number of Mutations Effect of Mutation
Missense/nonsense 256 substitutions of a single base-pair in coding regions, that cause a amino acid or stop/start codon change
Splicing 16 mutations that influence the mRNA splicing
Regulatory 0 different Regulation caused by substitution
Small deletions 26 micro-deletions (< 21 bp)
Small insertions 13 micro-insertions (<21 bp)
Small indels 4 micro-indels (<21 bp)
Gross deletions 3 deletion (>20 bp)
Gross insertions/duplications 1 insertion (>20 bp)
Complex rearrangements 16 rearangement of DNA fragments within the sequence
Repeat variations 0 different number of repeats
Total 335
Mutations found for gene symbol GBA on the database HGMD.

</figtable>

GBA is not affected by a regulatory mutations and repeated variations. The mutations on GBA do not only result to Gaucher's disease or influence its phenotype, but may also have an effect on the phenotype of the diseases Parkinson and Alzheimer. HGMD public (2008 update) provides 335 mutations for GBA (table 1). On HGMD Professional 2013.1, 380 mutations can be found.


The following table of missense/nonsense mutations on GBA shows an abridgment of 10 mutations out of all 256 known missense/nonsense mutation (<xr id="hgmd"/>)of the public version of HGMD. The high number of mutations shows the high liability of GBA on Gaucher causing mutations. Some position specific amino acids have a higher liability to causing a the Gaucher's disease, as more than one missense/nonsense mutation occur on that position (for example on sequence position 54 in <xr id="miss"/>).


<figtable id="miss">

Missense/nonsense mutations on GBA
Accession Number Codon change Amino acid change Codon Number
CM081634 cGGC-AGC Gly-Ser 49
CM057078 AGC-ATC Ser-Ile 51
CM044630 gGTG-ATG Val-Met 54
CM960691 gGTG-CTG Val-Leu 54
HM971738 TGT-TCT Cys-Ser 55
CM081630 AGT-AAT Ser-Asn 81
CM950560 ACA-ATA Thr-Ile 82
CM960692 GGG-GAG Gly-Glu 85
CM016030 gCGA-TGA Arg-Term 86
CM950561 aCGG-TGG Arg-Trp 87
First 10 missense/non-sense mutation (out of 256) listed on HGMD for GBA.

</figtable>

dbSNP

The available data in dbSNP (version 138) was released on April 25, 2013. It provides mutation information for the three organisms, Homo sapiens, Mus musculus and Bos taurus. The database contains single base nucleotide substitutions as well as short deletion and insertion polymorphisms. The database is provided by NCBI, which gets the research information from the National Human Genome Research Institute.

A point mutation can be classfied as synonymous or non-synonymous, caused by insertions and deletions. A synonymous snp has no effect on the resulting protein, as the mutating nucleotide still results into the same amino acid. A non-synonymous point mutation causes to a different amino acid. However, also a non-synonymous snp may have no effect on the protein structure. In case a snp appears on a postion which is not important for the protein structure or the mutated amino acids has a similar characteristic than its real amino acid, the structure of the protein is not affected and the protein function is still preserved. But in worst case, the point mutation generates a stop codon so that the protein is incomplete and thus not functional. Also snps on so called hot spots can destroy the protein structure and result to an inoperative protein.

In the database 150 mutation were found for Homo sapiens on the gene GBA. 61 of them are silent mutations. Some chosen silent mutations are listed in <xr id="dbsnp"/>.

<figtable id="dbsnp">

Silent mutations on GBA
mRNA Protein refNumber
Allele change Sequence position Residue Codon position
TCG ⇒ TCA 530 Ser 35 rs148001886
CCC ⇒ CCT 908 Pro 161 rs79767521
CTG ⇒ CTT 1262 Leu 279 rs371576958
Randomly chosen, silent mutations of GBA with accession numbers NM_001005741.2 (gene) and NP_001005741.1 (protein) on dbSNP.

</figtable>

"SNP Geneview Report" of the "gene" search of the GBA human gene which lists all mutations: [[1]].


SNPedia

"SNPedia selects everything that is worth to be stored." [2] SNPs with characteristics to significant medical or genealogical consequences or that are common, reproducible and/or have other historic or medical significance. gives a short summary of known information of a gene taken from literature and internet. As SNPedia is a wiki, those informations are most probably taken from Wikipedia. It refers to well known databases like OMIM or dbSNP as well as to some others like google, 23andMe, FamilyTreeDNA or National Geographic [3]. Informations from this side should be taken carefully, as not all content of SNPedia make a serious impression. It also links to a web service called Promethease which allows the user to check their own DNA against the database. Its last update took place on 16th May 2013. In the current version SNPedia contents information of SNPs about 78 genomes.

A search of GBA on SNPedia founds 48 SNPs on other webservices.

SNPdbe

  • The following information (if available) is given on each SAAS (single amino acid substitution):
    • Experimentally derived functional and structural impact
    • Predicted functional effect
    • Associated disease
    • Average heterozygosity
    • Experimental evidence of the nsSNP
    • Evolutionary conservation of wildtype and mutant amino acid
    • Link-outs to external databases
  • Last update: 2012-02-20 (updated to recent Swiss-Prot release (2012-01))
  • The information comes from various databases (SwissProt, PMD, dbSNP, 1000 Genomes) and SNP effect is predicted with SIFT and SNAP
  • Currently (2013-06-23) 159142 protein sequences from 2985 organisms are covered in SNPdbe and 1691464 SAASs are referenced, consisting of natural variants, SAASs from mutagenesis experiments and sequencing conflicts

<figtable id="snpdbe_human">

Human variants
Effect Number Percent
Observed functional effect 23121 2%
Disease associations 26842 3%
Observed functional effect and disease 1629 0.17%
Overall 967879 100%
Statistics about the human variants in SNPdbe.

</figtable>

Search for Gaucher disease delivered 174 entries, 147 from them from the human gene GBA and protein P04062. Note: as some of the mutation occur at the same position, there are only 121 distinct mutated positions from the subset of 147.

Most SNPs are not validated:

<figtable id="snpdbe_evidence">

Experimental evidence
Number of mutations Evidence type
120 Not validated
20 by cluster
3 by cluster,freq
2 1000Genome,freq,cluster
1 by freq
1 HapMap,freq,cluster
Statistics about the experimental evidence in SNPdbe.

</figtable>

Conservation score: Likelihood of observing either the wt (wildtype; green bar) or mt (mutant; red bar) at given position in the sequence. The longer the bar the higher the likelihood. The conservation score can be used as a first (simple) estimate of effect (disease causing) or no effect. There are three types of conservation scores: Pssm, Perc and Psic. There is a direct correlation between the length of the bars and Perc scores, however it is difficult to find a threshold to discriminate effect from no-effect. On the contrary, Pssm mt scores below 0 combined with Pssm wt scores above 0 imply very low occurrence of the mutant in comparison to the wild type protein, which implies that the mutation is deleterious (causes a negative effect). With this method we received 46 no-effect 101 effect mutations.


OMIM

  • daily updated
  • 21 844 entries (updated 11 June 2013)
  • gene entries → allelic variants (only selected mutations)
  • disease entries
  • relationship between genotype and phenotype (diseases)

For the GBA gene 48 mutations are found in OMIM (41 of them are referenced to dbSNP), which is a small number in comparison to the other databases. OMIM table view of GBA allelic variants.

SNP Databases Summary

under construction

<figtable id="databases">

SNP Databases
Information Database
HGMD dbSNP SNPedia SNPdbe OMIM
Type of information Only non-silent mutations in the coding region: disease-causing/associated mutations, disease-associated/functional polymorphisms. Mutation type/number/effect, associated disease phenotype, chromosomal location, gene symbol, reference of its first literature report Mutation information for Homo sapiens, Mus musculus and Bos taurus: SNPs, short deletion and insertion polymorphisms Mutation information collected from different databases For each SNP: experimentally derived functional and structural impact, predicted functional effect, associated disease, average heterozygosity, experimental evidence of the nsSNP, evolutionary conservation of wildtype and mutant amino acid, link-outs to external databases Gene entries - information about mutations from GWAs, allelic variants (only selected examples), disease entries, relationship between genotype and phenotype (diseases)
Source of information Literature, reported functional studies NCBI in collaboration with National Human Genome Research Institute Various databases (OMIM, dbSNP, 23andME, etc.), searching machines (google, wikipedia, etc.) Various databases (SwissProt, PMD, dbSNP, 1000 Genomes), SNP effect is predicted with SIFT and SNAP Full-text, referenced overviews
Last update Professional version: March 2013, free public version: from professional release 2008 April 25, 2013 May 16, 2013 February 20, 2012 daily updated
GBA mutations Total: 335, of them missense/nonsense SNPs: 256 Total: 432, of them silent SNPs: 59 48 SNPs Total: 147 SNPs (46 no-effect 101 effect) At least 48 deleterious SNPs (in "allelic variants" table)
Summary about the explored SNPs databases: HGMD, dbSNP, SNPedia, dbSNP and OMIM.

</figtable>

Mutation map

We extracted information about the point mutations in our protein GBA causing Gaucher disease from three different databases described above: HGMD, dbSNP and SNPdbe. For dbSNP, the contig NT_004487.19 was used. We mapped the mutations to the location on the reference protein sequence (NP_001005741.1, identical to the UniProt entry P04062) and combined the information about identical mutations. Three different types of mutations were extracted:

  • missense, which lead to amino acid exchange (from all databases)
  • nonsense, which lead to a premature termination of translation and end of the protein (only from HGMD)
  • synonymous, leading to a different codon, but encoding the same amino acid (only from dbSNP)

As the next step, the mutations were classified into

  • pathogenic (i.e. Gaucher disease causing) and
  • not pathogenic (non-disease causing).

All mutations from HGMD are pathogenic. In dbSNP, no such annotation is found. In SNPdbe we decided whether a mutation is pathogenic or not according to the conservation scores, as described above. If a mutation had at least one annotation that it causes Gaucher disease, we classified it as pathogenic, otherwise as not pathogenic.

Altogether 366 point mutations were collected our protein sequence, from them 246 disease causing and 120 non-disease causing (<xr id="mut_map"/>). Finally, we plotted the mutation according to the classes and the types using R (Figure 1).

<figtable id="mut_map">

AA position Mutation Type Pathogenic Accession Disease causing?
5 S-N missense N/A rs201985614 FALSE
13 K-R missense Gaucher disease ?; N/A CM065215; rs150466109 TRUE
14 P-S missense N/A rs371238435 FALSE
15 L-S missense N/A rs1141802 FALSE
16 S-G missense N/A rs1141804 FALSE
17 R-G missense N/A rs139626710 FALSE
19 S-N missense N/A rs376644484 FALSE
20 I-V missense N/A rs143187997 FALSE
27 G-G synonymous N/A rs1059731 FALSE
28 L-L synonymous N/A rs201330214 FALSE
35 S-S synonymous N/A rs148001886 FALSE
36 W-TERM nonsense Gaucher disease 1 CM980822 TRUE
39 G-D missense N/A rs200378040 FALSE
41 R-C missense N/A rs190207858 FALSE
46 K-E missense N/A rs142761046 FALSE
48 F-F synonymous N/A rs185884197 FALSE
49 G-S missense Gaucher disease CM081634 TRUE
51 S-I missense Gaucher disease CM057078 TRUE
54 V-L missense Gaucher disease; gaucher disease (SwissVar) CM960691; rs121908302 TRUE
54 V-M missense Gaucher disease CM044630 TRUE
55 C-S missense Gaucher disease; gaucher disease (SwissVar) HM971738; N/A TRUE
56 V-V synonymous N/A rs145773486 FALSE
62 C-Y missense N/A rs145888253 FALSE
63 D-D synonymous N/A rs74953658 FALSE
63 D-E missense N/A rs74953658 FALSE
63 D-N missense Gaucher disease 1; gaucher disease type 1 (SwissVar) CM050263; N/A TRUE
68 P-R missense N/A rs141061530 FALSE
72 A-A synonymous N/A rs151093421 FALSE
74 G-A missense N/A rs371592589 FALSE
74 G-S missense Gaucher disease ? CM065221 TRUE
75 T-N missense N/A rs373363286 FALSE
76 F-F synonymous N/A rs75954905 FALSE
76 F-L missense N/A rs75954905 FALSE
76 F-V missense Gaucher disease 1; N/A(gaucher disease (SwissVar)) CM970615; N/A TRUE
77 S-R missense N/A rs368786234 FALSE
78 R-C missense N/A rs146774384 FALSE
80 E-E synonymous N/A rs76337315 FALSE
80 E-K missense Gaucher disease 2; gaucher disease type 2 (SwissVar) CM983509; rs1141808 TRUE
81 S-N missense Gaucher disease CM081630 TRUE
81 S-S synonymous N/A rs1141810 FALSE
82 T-I missense Gaucher disease; N/A; gaucher disease (SwissVar) CM950560; rs1141811; rs1141811 TRUE
82 T-R missense N/A rs1141811 FALSE
83 R-C missense N/A rs1141812 FALSE
83 R-S missense N/A rs1141812 FALSE
85 G-E missense Gaucher disease; gaucher disease (SwissVar) CM960692; rs77829017 TRUE
86 R-Q missense N/A rs144173415 FALSE
86 R-TERM nonsense Gaucher disease CM016030 TRUE
87 R-Q missense Gaucher disease; N/A; N/A(gaucher disease (SwissVar)) CM071788; rs78769774; rs78769774 TRUE
87 R-R synonymous N/A rs78669556 FALSE
87 R-W missense Gaucher disease; N/A; gaucher disease (SwissVar). In severe Gaucher disease (GD) type 1 (PMD) CM950561; rs1141814; rs1141814 TRUE
92 M-T missense N/A rs1141815 FALSE
93 G-G synonymous N/A rs1141816 FALSE
99 H-R missense N/A rs1141820 FALSE
99 H-Y missense N/A rs1141818 FALSE
100 T-T synonymous N/A rs1141821 FALSE
105 L-P missense Gaucher disease CM057085 TRUE
108 L-L synonymous N/A rs368145008 FALSE
112 Q-TERM nonsense Gaucher disease CM057075 TRUE
113 K-TERM nonsense Gaucher disease CM970616 TRUE
117 V-A missense Gaucher disease CM081644 TRUE
118 K-N missense Gaucher disease; gaucher disease (SwissVar) CM960693; rs121908312 TRUE
124 M-T missense Gaucher disease CM081632 TRUE
129 A-A synonymous N/A rs79175920 FALSE
129 A-T missense Gaucher disease 1; gaucher disease (SwissVar) CM001161; N/A TRUE
141 N-S missense N/A rs374003673 FALSE
144 L-R missense Gaucher disease 1 CM020940 TRUE
146 S-L missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM980823; N/A TRUE
147 Y-C missense Gaucher disease CM082775 TRUE
148 F-V missense Gaucher disease 1 CM005404 TRUE
150 E-K missense Gaucher disease ? CM065220 TRUE
152 G-E missense Gaucher disease 1; gaucher disease (SwissVar) CM980824; N/A TRUE
156 N-D missense Gaucher disease 1; gaucher disease (SwissVar) CM001162; N/A TRUE
156 N-K missense N/A rs77019233 FALSE
158 I-I synonymous N/A rs147411159 FALSE
158 I-S missense Gaucher disease 1; N/A; gaucher disease type 1 (SwissVar) CM050264; rs77834747; rs77834747 TRUE
158 I-T missense Gaucher disease; gaucher disease (SwissVar) CM980825; N/A TRUE
159 R-Q missense Gaucher disease 1; gaucher disease (SwissVar) CM880035; rs79653797 TRUE
159 R-R synonymous N/A rs75249684 FALSE
159 R-W missense Gaucher disease; gaucher disease (SwissVar) CM960694; rs439898 TRUE
160 V-A missense Gaucher disease ? CM057093 TRUE
161 P-L missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM052240; rs79637617; rs79637617 TRUE
161 P-P synonymous N/A rs79767521 FALSE
161 P-S missense Gaucher disease; gaucher disease (SwissVar) CM930289; rs121908299 TRUE
162 M-I missense N/A rs77959976 FALSE
162 M-T missense Gaucher disease CM044627 TRUE
162 M-V missense Gaucher disease; N/A; N/A(gaucher disease (SwissVar)) CM057081; rs377325220; N/A TRUE
166 D-V missense Gaucher disease; N/A; gaucher disease (SwissVar) CM057089; rs79796061; rs79796061 TRUE
170 R-C missense Gaucher disease 2; gaucher disease type 1 gaucher disease type 2 (SwissVar) CM983510; N/A TRUE
170 R-L missense Gaucher disease 2; gaucher disease (SwissVar) CM000161; rs75690705 TRUE
173 T-I missense Gaucher disease 1; gaucher disease (SwissVar) CM001163; rs78657146 TRUE
173 T-P missense Gaucher disease 1; gaucher disease (SwissVar) CM980826; N/A TRUE
174 Y-TERM nonsense Gaucher disease 1 CM001164 TRUE
175 A-E missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM020710; rs79660787 TRUE
179 D-H missense Gaucher disease 1; N/A; gaucher disease (SwissVar) CM910171; rs147138516; rs147138516 TRUE
182 Q-R missense N/A rs375193074 FALSE
191 E-A missense Gaucher disease CM081639 TRUE
196 K-N missense Gaucher disease ? CM057074 TRUE
196 K-Q missense Gaucher disease 2; N/A(gaucher disease (SwissVar)) CM910172; rs121908297 TRUE
198 P-L missense Gaucher disease; gaucher disease (SwissVar) CM980827; rs80222298 TRUE
198 P-T missense Gaucher disease; gaucher disease (SwissVar) CM022012; N/A TRUE
200 I-N missense gaucher disease (SwissVar) rs77933015 TRUE
200 I-S missense Gaucher disease; gaucher disease (SwissVar) CM980828; rs77933015 TRUE
201 H-P missense Gaucher disease 1; gaucher disease (SwissVar) CM020711; rs76500263 TRUE
202 R-TERM nonsense Gaucher disease CM980829 TRUE
208 Q-TERM nonsense Gaucher disease 1 CM980830 TRUE
209 R-C missense Gaucher disease 1; gaucher disease (SwissVar) CM001165; N/A TRUE
209 R-P missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM980831; N/A TRUE
210 P-P synonymous N/A rs201615998 FALSE
211 V-I missense N/A rs188760929 FALSE
212 S-TERM nonsense Gaucher disease CM950562 TRUE
213 L-F missense Gaucher disease ?; N/A; N/A(gaucher disease (SwissVar)) CM057076; rs374591570; N/A TRUE
213 L-L synonymous N/A rs78659905 FALSE
215 A-D missense Gaucher disease; gaucher disease (SwissVar) CM940805; N/A TRUE
217 P-P synonymous N/A rs76717906 FALSE
217 P-S missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM950563; N/A TRUE
218 W-TERM nonsense Gaucher disease CM970617 TRUE
219 T-P missense Gaucher disease CM081641 TRUE
221 P-L missense Gaucher disease 2; N/A; gaucher disease type 1 (SwissVar) CM041347; rs80205046; rs80205046 TRUE
221 P-P synonymous N/A rs76727497 FALSE
221 P-T missense Gaucher disease; gaucher disease (SwissVar) CM940806; N/A TRUE
223 W-R missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM001166; rs61748906; rs61748906 TRUE
224 L-F missense Gaucher disease ?; N/A(gaucher disease (SwissVar)) CM057091; N/A TRUE
224 L-L synonymous N/A rs76682322 FALSE
227 N-K missense Gaucher disease; N/A; gaucher disease (SwissVar) CM980832; rs381418; rs381418 TRUE
227 N-S missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM960695; rs364897 TRUE
228 G-V missense Gaucher disease; N/A; gaucher disease (SwissVar) CM970618; rs78911246; rs78911246 TRUE
229 A-A synonymous N/A rs75370695 FALSE
229 A-E missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM000162; rs75636769; rs75636769 TRUE
229 A-T missense Gaucher disease 3; N/A(gaucher disease (SwissVar)) CM001167; N/A TRUE
230 V-E missense Gaucher disease 1; N/A; gaucher disease type 1 (SwissVar) CM050265; rs381427; rs381427 TRUE
230 V-G missense Gaucher disease; N/A; gaucher disease type 1 (SwissVar) CM980833; rs381427; rs381427 TRUE
232 G-E missense gaucher disease (SwissVar) N/A TRUE
232 G-G synonymous N/A rs375731497 FALSE
232 G-W missense Gaucher disease CM092866 TRUE
234 G-E missense Gaucher disease; N/A; gaucher disease (SwissVar) CM970619; rs74462743; rs74462743 TRUE
234 G-W missense Gaucher disease; gaucher disease (SwissVar) CM990680; N/A TRUE
235 S-P missense Gaucher disease; gaucher disease (SwissVar) CM992893; rs1064644 TRUE
235 S-S synonymous N/A rs76158190 FALSE
236 L-F missense Gaucher disease CM057077 TRUE
236 L-L synonymous N/A rs372785813 FALSE
236 L-P missense Gaucher disease ? CM057087 TRUE
237 K-E missense Gaucher disease 2; gaucher disease (SwissVar) CM020712; N/A TRUE
237 K-K synonymous N/A rs74486098 FALSE
240 P-P synonymous N/A rs376613535 FALSE
241 G-E missense Gaucher disease; N/A; gaucher disease (SwissVar) CM992894; rs77451368; rs77451368 TRUE
241 G-R missense Gaucher disease; N/A(gaucher disease (SwissVar). In severe neuronopathic (type 2) Gaucher's disease: This mutant acid beta-glucosidase persists in the patient's fibroblasts as a mannose-rich polypeptide in the endoplasmic reticulum and is not transported to the lysosomes. (PMD)) CM940807; N/A TRUE
244 Y-C missense Gaucher disease 1; N/A; N/A(gaucher disease (SwissVar)) CM990681; rs76026102; rs76026102 TRUE
248 W-R missense Gaucher disease CM081637 TRUE
249 A-V missense Gaucher disease ? CM065217 TRUE
251 Y-H missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM930290; rs121908300 TRUE
252 F-C missense Gaucher disease HM971754 TRUE
252 F-I missense Gaucher disease 3; N/A(gaucher disease (SwissVar)) CM910173; rs381737 TRUE
252 F-L missense N/A rs79945741 FALSE
255 F-V missense Gaucher disease CM940808 TRUE
255 F-Y missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM900103; rs74500255 TRUE
259 Y-C missense Gaucher disease ? CM065219 TRUE
270 T-R missense Gaucher disease; gaucher disease (SwissVar) CM022013; rs76725886 TRUE
272 E-D missense Gaucher disease CM081640 TRUE
272 E-TERM nonsense Gaucher disease 2 CM990682 TRUE
275 P-T missense Gaucher disease CM077546 TRUE
276 S-P missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM980834; N/A TRUE
278 G-V missense Gaucher disease CM081643 TRUE
279 L-L synonymous N/A rs371576958 FALSE
281 S-N missense N/A rs138246400 FALSE
282 G-V missense Gaucher disease CM081642 TRUE
283 Y-H missense Gaucher disease CM081631 TRUE
284 P-H missense Gaucher disease ? CM057082 TRUE
288 L-Q missense Gaucher disease CM077543 TRUE
290 F-L missense Gaucher disease 2; gaucher disease (SwissVar) CM020713; rs121908313 TRUE
294 H-Q missense Gaucher disease 2; N/A(gaucher disease type 1 (SwissVar)) CM000163; N/A TRUE
296 R-Q missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM940809; rs78973108 TRUE
296 R-TERM nonsense Gaucher disease 1 CM980835 TRUE
298 F-L missense Gaucher disease 2; N/A(gaucher disease (SwissVar)) CM000164; N/A TRUE
299 I-T missense Gaucher disease 2 CM053270 TRUE
301 R-C missense N/A rs374117599 FALSE
301 R-H missense N/A rs140955685 FALSE
303 L-I missense N/A(gaucher disease (SwissVar)) N/A FALSE
304 G-D missense Gaucher disease; N/A; gaucher disease (SwissVar) CM980836; rs80116658; rs80116658 TRUE
305 P-A missense Gaucher disease CM057095 TRUE
305 P-L missense Gaucher disease 2 HM971737 TRUE
305 P-R missense Gaucher disease; N/A; gaucher disease (SwissVar) CM950564; rs79215220; rs79215220 TRUE
306 T-I missense N/A rs199628072 FALSE
306 T-T synonymous N/A rs371856161 FALSE
308 A-T missense N/A rs368425393 FALSE
310 S-N missense Gaucher disease; N/A; N/A(gaucher disease (SwissVar)) CM970620; rs74731340; rs74731340 TRUE
318 L-P missense Gaucher disease CM081635 TRUE
324 R-C missense Gaucher disease; gaucher disease (SwissVar) CM940810; N/A TRUE
324 R-H missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM000165; rs79696831; rs79696831 TRUE
327 L-P missense Gaucher disease CM077544 TRUE
328 P-L missense Gaucher disease; gaucher disease (SwissVar) CM920298; rs121908298 TRUE
329 H-Q missense N/A rs142662866 FALSE
335 L-L missense Gaucher disease 1 ? CM080379 TRUE
335 L-V missense Gaucher disease 1 CM082770 TRUE
338 P-A missense N/A rs374463271 FALSE
342 K-I missense Gaucher disease; N/A; N/A(gaucher disease (SwissVar)) CM980837; rs77714449; rs77714449 TRUE
342 K-K synonymous N/A rs1064646 FALSE
343 Y-C missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM000166; rs77321207; rs77321207 TRUE
343 Y-TERM nonsense Gaucher disease 3 CM001168 TRUE
344 V-L missense Gaucher disease ? CM057098 TRUE
345 H-Y missense N/A rs181720335 FALSE
346 G-G synonymous N/A rs1064647 FALSE
348 A-V missense Gaucher disease 1; gaucher disease (SwissVar) CM910174; rs78396650 TRUE
349 V-I missense N/A rs371083513 FALSE
350 H-R missense Gaucher disease 2 CM993703 TRUE
351 W-C missense Gaucher disease 1; N/A(gaucher disease (SwissVar)) CM910175; rs121908304 TRUE
351 W-R missense Gaucher disease CM074886 TRUE
352 Y-H missense Gaucher disease; gaucher disease (SwissVar) CM960696; N/A TRUE
352 Y-Y synonymous N/A rs79311125 FALSE
354 D-H missense Gaucher disease; gaucher disease (SwissVar) CM950565; N/A TRUE
357 A-D missense Gaucher disease; N/A; N/A(gaucher disease (SwissVar)) CM950566; rs78188205; rs78188205 TRUE
358 P-A missense Gaucher disease ? CM057094 TRUE
358 P-S missense Gaucher disease CM077547 TRUE
362 T-I missense Gaucher disease; gaucher disease (SwissVar) CM920299; rs76539814 TRUE
363 L-P missense Gaucher disease; gaucher disease (SwissVar) CM980838; N/A TRUE
363 L-Q missense Gaucher disease 1 CM076208 TRUE
364 G-G synonymous N/A rs143222798 FALSE
364 G-R missense Gaucher disease 2; N/A(gaucher disease (SwissVar)) CM900104; rs121908305 TRUE
364 G-W missense Gaucher disease CM014190 TRUE
365 E-E synonymous N/A rs80317710 FALSE
365 E-K missense Gaucher disease 1 ?; N/A(gaucher disease (SwissVar)) CM910176; rs2230288 TRUE
368 R-C missense N/A rs374306700 FALSE
368 R-H missense N/A rs1064648 FALSE
370 F-S missense Gaucher disease CM081647 TRUE
375 L-P missense Gaucher disease CM044629 TRUE
380 A-T missense Gaucher disease; gaucher disease (SwissVar) CM980839; N/A TRUE
381 C-G missense Gaucher disease 2; N/A(gaucher disease (SwissVar)) CM900105; rs121908306 TRUE
381 C-R missense Gaucher disease 1 CM025357 TRUE
381 C-Y missense Gaucher disease CM057097 TRUE
387 W-G missense Gaucher disease CM081638 TRUE
388 E-E synonymous N/A rs75391747 FALSE
388 E-K missense Gaucher disease ?; gaucher disease (SwissVar) CM057092; N/A TRUE
389 Q-TERM nonsense Gaucher disease 1 CM020714 TRUE
391 V-L missense Gaucher disease; gaucher disease (SwissVar) CM970621; N/A TRUE
391 V-M missense Gaucher disease CM077548 TRUE
392 R-G missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM980840; rs121908308 TRUE
392 R-Q missense N/A rs11558184 FALSE
392 R-W missense Gaucher disease ?; gaucher disease (SwissVar) CM057090; N/A TRUE
394 G-D missense Gaucher disease HM971755 TRUE
395 S-F missense Gaucher disease 1 HM971756 TRUE
396 W-C missense Gaucher disease CM093532 TRUE
396 W-TERM nonsense Gaucher disease CM043998 TRUE
398 R-Q missense Gaucher disease; N/A; gaucher disease (SwissVar) CM920300; rs74979486; rs74979486 TRUE
398 R-TERM nonsense Gaucher disease CM940811 TRUE
400 M-I missense Gaucher disease; N/A; gaucher disease (SwissVar) CM022014; rs149487315; rs149487315 TRUE
402 Y-C missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM052241; rs76228122; rs76228122 TRUE
403 S-N missense Gaucher disease CM074884 TRUE
403 S-R missense Gaucher disease CM044628 TRUE
403 S-T missense Gaucher disease 1; gaucher disease (SwissVar) CM910177; rs121908307 TRUE
405 S-G missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM970622; N/A TRUE
405 S-N missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM980841; N/A TRUE
405 S-R missense N/A rs75528494 FALSE
405 S-T missense Gaucher disease HM971759 TRUE
408 T-M missense Gaucher disease; N/A; gaucher disease (SwissVar) CM960697; rs75548401; rs2230289 TRUE
408 T-T synonymous N/A rs138498426 FALSE
409 N-K missense Gaucher disease ? CM057073 TRUE
409 N-S missense Gaucher disease 1; N/A(gaucher disease type 1 (SwissVar)) CM880036; rs76763715 TRUE
410 L-L synonymous N/A rs74498117 FALSE
410 L-V missense Gaucher disease; gaucher disease (SwissVar) CM040422; rs121908314 TRUE
414 V-L missense Gaucher disease; gaucher disease (SwissVar) CM970623; N/A TRUE
416 G-G synonymous N/A rs75034092 FALSE
416 G-S missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM940812; rs121908311 TRUE
417 W-C missense N/A rs76014919 FALSE
417 W-G missense Gaucher disease; gaucher disease (SwissVar) CM940813; N/A TRUE
417 W-TERM nonsense Gaucher disease CM057096 TRUE
419 D-A missense Gaucher disease; N/A; gaucher disease (SwissVar) CM930291; rs77284004; rs77284004 TRUE
419 D-E missense N/A rs78715199 FALSE
419 D-H missense Gaucher disease; gaucher disease (SwissVar) CM054757; N/A TRUE
419 D-N missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM940814; N/A TRUE
419 D-Y missense Gaucher disease CM082774 TRUE
420 W-TERM nonsense Gaucher disease CM081645 TRUE
421 N-K missense Gaucher disease 2; gaucher disease (SwissVar) CM052242; N/A TRUE
422 L-I missense N/A rs187143994 FALSE
422 L-R missense Gaucher disease 2 CM052243 TRUE
423 A-D missense Gaucher disease CM077545 TRUE
424 L-P missense Gaucher disease 2 CM052244 TRUE
426 P-L missense Gaucher disease; gaucher disease (SwissVar) CM960698; N/A TRUE
426 P-P synonymous N/A rs201499639 FALSE
427 E-K missense N/A rs149171124 FALSE
427 E-TERM nonsense Gaucher disease CM057083 TRUE
428 G-E missense Gaucher disease 2; gaucher disease (SwissVar) CM980842; N/A TRUE
429 G-R missense Gaucher disease; gaucher disease (SwissVar) CM057079; N/A TRUE
430 P-L missense Gaucher disease 1; N/A; gaucher disease (SwissVar) CM980843; rs76910485; rs76910485 TRUE
431 N-I missense Gaucher disease 2; N/A; gaucher disease (SwissVar) CM980844; rs77738682; rs77738682 TRUE
432 W-L missense Gaucher disease CM081646 TRUE
432 W-R missense Gaucher disease; gaucher disease (SwissVar) CM980845; N/A TRUE
433 V-L missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM890054; rs80356769 TRUE
434 R-C missense Gaucher disease 1 CM065218 TRUE
434 R-P missense Gaucher disease 1 CM005403 TRUE
435 N-T missense Gaucher disease; N/A; gaucher disease type 1 (SwissVar) CM960699; rs75385858; rs75385858 TRUE
436 F-S missense Gaucher disease; N/A; gaucher disease (SwissVar) CM057099; rs75243000; rs75243000 TRUE
437 V-F missense Gaucher disease 2 CM993704 TRUE
437 V-I missense Gaucher disease 1 CM065222 TRUE
437 V-L missense Gaucher disease 3; N/A(gaucher disease type 3 (SwissVar)) CM960700; N/A TRUE
437 V-V synonymous N/A rs79032178 FALSE
438 D-D synonymous N/A rs75090908 FALSE
438 D-E missense N/A rs75090908 FALSE
438 D-N missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM940815; N/A TRUE
438 D-Y missense Gaucher disease 1; gaucher disease (SwissVar) CM001169; N/A TRUE
440 P-L missense Gaucher disease 1; N/A(gaucher disease type 1 (SwissVar)) CM990683; rs74598136 TRUE
441 I-F missense Gaucher disease 3; gaucher disease (SwissVar) CM020715; N/A TRUE
441 I-T missense Gaucher disease; N/A; gaucher disease (SwissVar) CM970624; rs75564605; rs75564605 TRUE
444 D-V missense Gaucher disease CM093533 TRUE
446 T-N missense N/A rs202221385 FALSE
448 D-E missense N/A rs78802049 FALSE
448 D-G missense Gaucher disease CM057088 TRUE
448 D-H missense Gaucher disease 2; gaucher disease (SwissVar). Gaucher disease (PMD) CM900106; rs1064651 TRUE
448 D-V missense Gaucher disease; gaucher disease (SwissVar) CM940816; rs77369218 TRUE
450 F-I missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM980846; N/A TRUE
450 F-L missense N/A rs77035024 FALSE
451 Y-H missense Gaucher disease 1; N/A(gaucher disease (SwissVar)) CM980847; N/A TRUE
451 Y-Y synonymous N/A rs78346899 FALSE
452 K-Q missense Gaucher disease; gaucher disease (SwissVar) CM970625; N/A TRUE
453 Q-R missense Gaucher disease CM057080 TRUE
453 Q-TERM nonsense Gaucher disease CM960701 TRUE
454 P-R missense Gaucher disease 2; gaucher disease (SwissVar) CM890055; rs121908295 TRUE
455 M-I missense N/A rs80020805 FALSE
455 M-V missense Gaucher disease 2; gaucher disease (SwissVar) CM052245; N/A TRUE
456 F-F synonymous N/A rs79185870 FALSE
456 F-L missense N/A rs79185870 FALSE
456 F-V missense Gaucher disease 1; gaucher disease (SwissVar) CM940817; N/A TRUE
457 Y-C missense Gaucher disease; N/A; gaucher disease (SwissVar) CM940818; rs74752878; rs74752878 TRUE
460 G-D missense Gaucher disease 1; gaucher disease type 1 (SwissVar) CM050266; N/A TRUE
464 K-E missense Gaucher disease; gaucher disease (SwissVar) CM920301; N/A TRUE
464 K-N missense N/A rs79226895 FALSE
465 F-V missense Gaucher disease CM085444 TRUE
471 Q-H missense N/A rs12747811 FALSE
472 R-G missense Gaucher disease CM970626 TRUE
472 R-S missense Gaucher disease CM081629 TRUE
479 Q-P missense N/A rs144389406 FALSE
483 L-L synonymous N/A rs369966551 FALSE
483 L-P missense Gaucher disease 2; gaucher disease type 1 gaucher disease type 2 (SwissVar). In Gaucher disease (GD) (PMD) CM870010; rs421016 TRUE
483 L-R missense Gaucher disease; gaucher disease (SwissVar) CM940819; N/A TRUE
485 A-A synonymous N/A rs199928507 FALSE
485 A-P missense Gaucher disease; gaucher disease (SwissVar) CM980848; N/A TRUE
490 H-L missense N/A rs76071730 FALSE
490 H-P missense N/A rs76071730 FALSE
490 H-R missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM022015; rs76071730 TRUE
491 P-P synonymous N/A rs149257166 FALSE
495 A-A synonymous N/A rs375973565 FALSE
495 A-P missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM900107; rs368060 TRUE
498 V-V synonymous N/A rs371779859 FALSE
499 V-L missense N/A rs369068553 FALSE
499 V-M missense Gaucher disease 1 HM971757 TRUE
499 V-V synonymous N/A; N/A rs421050; rs1135675 FALSE
500 L-L synonymous N/A rs189380051 FALSE
500 L-P missense Gaucher disease ?; gaucher disease (SwissVar) CM057086; N/A TRUE
501 N-K missense Gaucher disease; gaucher disease (SwissVar) CM972851; N/A TRUE
501 N-S missense Gaucher disease ? CM057072 TRUE
502 R-C missense Gaucher disease; gaucher disease (SwissVar) CM900108; rs80356771 TRUE
502 R-H missense Gaucher disease CM074885 TRUE
502 R-P missense Gaucher disease ?; N/A(gaucher disease (SwissVar)) CM057084; N/A TRUE
504 S-F missense N/A rs150246414 FALSE
507 V-M missense N/A rs370349398 FALSE
509 L-H missense N/A rs113825752 FALSE
509 L-R missense N/A rs113825752 FALSE
513 D-D synonymous N/A rs77409925 FALSE
513 D-E missense N/A rs77409925 FALSE
513 D-Y missense Gaucher disease 2; gaucher disease type 2 (SwissVar) CM980849; N/A TRUE
517 G-S missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM930292; rs121908301 TRUE
519 L-P missense Gaucher disease CM081636 TRUE
527 S-P missense Gaucher disease 2 CM004522 TRUE
528 I-T missense Gaucher disease ? CM065216 TRUE
530 T-I missense Gaucher disease 3; gaucher disease type 3 (SwissVar) CM960702; rs78016673 TRUE
534 R-C missense N/A rs146519305 FALSE
535 R-C missense Gaucher disease; gaucher disease (SwissVar) CM920302; N/A TRUE
535 R-H missense Gaucher disease; N/A(gaucher disease (SwissVar)) CM930293; rs75822236 TRUE
Information about the point mutations of the GBA gene/protein extracted from the HGMD, dbSNP and SNPdbe databases. The mutations are divided into Gaucher disease causing (dc) or non-disease causing (non-dc), as well as into missense, nonsense and synonymous.

</figtable>

As expected, all synonymous mutations are not disease causing, because they do not change the amino acid. And most nonsense mutations are disease causing, because a premature termination usually results in a shortened and dis-functional protein. In our case even all the nonsense mutations are deleterious. Missense mutation can have a negative effect or not, for our protein most of them do.

It can be seen in the map that there are some mutation hot-spots, i.e. many mutations concentrated in some area of the sequence. For example, around the positions 150 and 200-250 there are disease causing mutation hot-spots. The longest hot-spot with the most disease causing mutations lies in the area between the positions 400 and 450.

References

Adrienne Kitts and Stephen Sherry. The Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation. Chapter 5 in: The NCBI Handbook. Created: October 9, 2002; Last Update: February 2, 2011

Christian Schaefer, Alice Meier, Burkhard Rost, Yana Bromberg (2012). SNPdbe: Constructing an nsSNP functional impacts database. Bioinformatics 28(4):601-602.

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