The p.Gly395Ala variant in GLA has been reported in up to 10 Southern Italian families with Fabry disease (PMID: 21896204, 29487688, 27825144), and has been identified in 0.0024% (2/81904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375661583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry Disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar as a VUS by Invitae (ID: 405511). In vitro functional studies provide some evidence that the p.Gly395Ala variant may slightly impact protein function through decreased enzyme function (PMID: 23935525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21896204, 29487688, 27825144). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP4, PM2_supporting, PP3, PS4_supporting, PS3_supporting (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.1184G>C (p.Gly395Ala)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000169.3(GLA):c.1184G>C (p.Gly395Ala)
Variation ID: 405511 Accession: VCV000405511.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq22.1 X: 101397915 (GRCh38) [ NCBI UCSC ] X: 100652903 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 17, 2017 Apr 20, 2024 Dec 13, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.1184G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Gly395Ala missense NM_000169.2(GLA):c.1184G>C missense NM_001199973.2:c.300+2458C>G intron variant NM_001199974.2:c.177+6093C>G intron variant NM_001406747.1:c.1307G>C NP_001393676.1:p.Gly436Ala missense NR_164783.1:n.1263G>C non-coding transcript variant NR_176252.1:n.1114G>C non-coding transcript variant NR_176253.1:n.1321G>C non-coding transcript variant NC_000023.11:g.101397915C>G NC_000023.10:g.100652903C>G NG_007119.1:g.15049G>C LRG_672:g.15049G>C LRG_672t1:c.1184G>C LRG_672p1:p.Gly395Ala - Protein change
- G395A, G436A
- Other names
- -
- Canonical SPDI
- NC_000023.11:101397914:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7 | 1257 | |
| RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1295 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV000462655.15 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 27, 2023 | RCV003488603.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422793.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
|
Comment:
The p.Gly395Ala variant in GLA has been reported in up to 10 Southern Italian families with Fabry disease (PMID: 21896204, 29487688, 27825144), and has been … (more)
The p.Gly395Ala variant in GLA has been reported in up to 10 Southern Italian families with Fabry disease (PMID: 21896204, 29487688, 27825144), and has been identified in 0.0024% (2/81904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375661583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry Disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar as a VUS by Invitae (ID: 405511). In vitro functional studies provide some evidence that the p.Gly395Ala variant may slightly impact protein function through decreased enzyme function (PMID: 23935525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21896204, 29487688, 27825144). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP4, PM2_supporting, PP3, PS4_supporting, PS3_supporting (Richards 2015). (less)
|
|
|
Uncertain significance
(Aug 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543774.4
First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine with alanine at codon 395 of the GLA protein (p.Gly395Ala). The glycine residue is highly conserved and there is a … (more)
This sequence change replaces glycine with alanine at codon 395 of the GLA protein (p.Gly395Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs375661583, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 21896204, 27825144, 29487688, 30477121). ClinVar contains an entry for this variant (Variation ID: 405511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235151.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Apr 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357513.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain Significance
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004821929.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 5
|
|
|
Uncertain significance
(Oct 20, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081330.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This sequence change replaces glycine with alanine at codon 395 of the GLA protein (p.Gly395Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs375661583, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 21896204, 27825144, 29487688, 30477121). ClinVar contains an entry for this variant (Variation ID: 405511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The p.Gly395Ala variant in GLA has been reported in up to 10 Southern Italian families with Fabry disease (PMID: 21896204, 29487688, 27825144), and has been identified in 0.0024% (2/81904) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375661583). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry Disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar as a VUS by Invitae (ID: 405511). In vitro functional studies provide some evidence that the p.Gly395Ala variant may slightly impact protein function through decreased enzyme function (PMID: 23935525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype that is consistent with disease (PMID: 21896204, 29487688, 27825144). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP4, PM2_supporting, PP3, PS4_supporting, PS3_supporting (Richards 2015).
Comment:
This sequence change replaces glycine with alanine at codon 395 of the GLA protein (p.Gly395Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs375661583, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 21896204, 27825144, 29487688, 30477121). ClinVar contains an entry for this variant (Variation ID: 405511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces glycine with alanine at codon 395 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant leads to a 13-24% level of residual GLA enzyme activity when expressed in HEK293 cells (PMID: 21598360). This variant has been reported in a few individuals and families affected with Fabry disease (PMID: 26880903, 27825144, 29487688, 30477121, 35971858, 36709535), in an individual suspected of having Fabry disease (PMID: 21896204), and in five asymptomatic relatives of the affected carriers (PMID: 29487688, 32806660). This variant has been identified in 2/183463 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Patient reported quality of life and medication adherence in Fabry disease patients treated with migalastat: A prospective, multicenter study. | Müntze J | Molecular genetics and metabolism | 2023 | PMID: 36709535 |
| X-chromosomal inactivation patterns in women with Fabry disease. | Wagenhäuser L | Molecular genetics & genomic medicine | 2022 | PMID: 35971858 |
| Cerebral Hemodynamic Changes to Transcranial Doppler in Asymptomatic Patients with Fabry's Disease. | Vagli C | Brain sciences | 2020 | PMID: 32806660 |
| Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease? | Duro G | International journal of molecular sciences | 2018 | PMID: 30477121 |
| Fabry disease and multiple sclerosis misdiagnosis: the role of family history and neurological signs. | Colomba P | Oncotarget | 2018 | PMID: 29487688 |
| Genetic variants associated with gastrointestinal symptoms in Fabry disease. | Di Martino MT | Oncotarget | 2016 | PMID: 27825144 |
| Gastrointestinal Symptoms of Patients with Fabry Disease. | Pensabene L | Gastroenterology research and practice | 2016 | PMID: 26880903 |
| Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease. | Lukas J | PLoS genetics | 2013 | PMID: 23935525 |
| Genetic screening of Fabry patients with EcoTILLING and HRM technology. | Bono C | BMC research notes | 2011 | PMID: 21896204 |
| A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease. | Wu X | Human mutation | 2011 | PMID: 21598360 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/26a93cec-a19a-458c-be90-722f291067f6 | - | - | - | - |
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Text-mined citations for rs375661583 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.