ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.239G>A (p.Gly80Asp)
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.
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.
Likely pathogenic(1); Uncertain significance(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.239G>A (p.Gly80Asp)
Variation ID: 217380 Accession: VCV000217380.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101403941 (GRCh38) [ NCBI UCSC ] X: 100658929 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 11, 2016 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.239G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Gly80Asp missense NM_001199973.2:c.301-7995C>T intron variant NM_001199974.2:c.178-7995C>T intron variant NR_164783.1:n.261G>A non-coding transcript variant NC_000023.11:g.101403941C>T NC_000023.10:g.100658929C>T NG_007119.1:g.9023G>A NG_016327.1:g.739C>T LRG_672:g.9023G>A LRG_672t1:c.239G>A LRG_672p1:p.Gly80Asp P06280:p.Gly80Asp - Protein change
- G80D
- Other names
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- Canonical SPDI
- NC_000023.11:101403940:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein activity Variation Ontology [VariO:0053]
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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.
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0.00026 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00026
1000 Genomes Project 30x 0.00042
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1243 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1274 |
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. |
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Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV000209421.22 | |
drug response (1) |
no assertion criteria provided
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Jan 1, 2014 | RCV000209815.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 18, 2020 | RCV000732705.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 13, 2023 | RCV000993846.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 17, 2022 | RCV002444816.5 |
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. |
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Uncertain significance
(Mar 29, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000860685.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002054360.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Uncertain significance
(Jul 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919435.4
First in ClinVar: Jun 02, 2019 Last updated: Aug 26, 2023 |
Comment:
Variant summary: GLA c.239G>A (p.Gly80Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.239G>A (p.Gly80Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183388 control chromosomes (gnomAD). c.239G>A was initially reported in the literature in three male and five female individuals in a study of patients undergoing testing for Fabry disease at a commercial laboratory (Lukas_2016). It was described as a mild variant shown to have reduced alpha-Gal-A enzyme activity (29.3% of normal) in transfected cells and was associated with slightly elevated biomarker (lyso-Gb3) values in those with the variant. Subsequently, this variant has also been reported in one case of sudden unexplained death associated with cardiac disease (Lin_2017), an Argentinian male dialysis patient with non-confirmed Fabry disease (Frabasil_2019), one unpublished case report of a patient with autism and learning diffculties but not clinically diagnosed with Fabry disease (Gupta_2019), in several unaffected Eucadorian Hispanic infants in a NY pilot NBS program who were not diagnosed with and had no family history of Fabry disease (Wasserstein_2019), and in a male individual given a clinical diagnosis of late onset Fabry disease (Delarosa-Rodriguez_2021). Several of these studies report that the variant is associated with reduced alpha-Gal-A activity in plasma and/or isolated leukocytes (Frabasil_2019, Wasserstein_2019, Gupta_2019, Delarosa-Rodriguez_2021), however it also has a fairly high frequency reported in the admixed American population (Wasserstein_2019). Therefore, it is currently unclear whether this reduced, but significant residual level of activity associated with the variant is either insufficient to manifest as a clinical phenotype or is instead likely to result in the late onset form of the disease. The following publications have been ascertained in the context of this evaluation (PMID: 33527381, 31392112, 29247119, 26415523, 30093709). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either VUS (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV002052121.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with aspartic acid at codon 80 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glycine with aspartic acid at codon 80 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant leads to 29.3% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in three individuals referred for Fabry disease genetic testing (PMID: 26415523), one individual affected with sudden unexplained death (PMID: 29247119), eight unrelated newborns without a family history of Fabry disease (PMID: 30093709), one individual undergoing dialysis but not diagnosed with Fabry disease (PMID: 31392112), as well as in an individual affected with late-onset Fabry disease with renal symptoms (PMID: 33527381). Most of these carriers were males who usually showed high residual GLA enzyme activity and slightly elevated globotriaosylsphingosine (lyso-Gb3) levels (PMID: 26415523, 30093709, 31392112, 33527381). This variant has not been identified 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)
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Likely pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000748699.8
First in ClinVar: Mar 11, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 80 of the GLA protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 80 of the GLA protein (p.Gly80Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with predominantly late onset Fabry disease and/or low alpha-galactosidase activity (PMID: 26415523, 33527381; Invitae). ClinVar contains an entry for this variant (Variation ID: 217380). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 26415523). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002791618.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(May 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003816838.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain Significance
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004821937.1
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)
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Comment:
This missense variant replaces glycine with aspartic acid at codon 80 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glycine with aspartic acid at codon 80 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant leads to 29.3% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in three individuals referred for Fabry disease genetic testing (PMID: 26415523), one individual affected with sudden unexplained death (PMID: 29247119), eight unrelated newborns without a family history of Fabry disease (PMID: 30093709), one individual undergoing dialysis but not diagnosed with Fabry disease (PMID: 31392112), as well as in an individual affected with late-onset Fabry disease with renal symptoms (PMID: 33527381). Most of these carriers were males who usually showed high residual GLA enzyme activity and slightly elevated globotriaosylsphingosine (lyso-Gb3) levels (PMID: 26415523, 30093709, 31392112, 33527381). This variant has not been identified 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: 4
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Uncertain significance
(Nov 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002732551.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.239G>A (p.G80D) alteration is located in coding exon 2 of the GLA gene. This alteration results from a G to A substitution at nucleotide … (more)
The c.239G>A (p.G80D) alteration is located in coding exon 2 of the GLA gene. This alteration results from a G to A substitution at nucleotide position 239, causing the glycine (G) at amino acid position 80 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in individuals of Fabry disease cohorts, a renal failure cohort, and a sudden unexplained death cohort; however, clinical details were limited in some cases (Lukas, 2016; Lin, 2017; Frabasil, 2019; Wasserstein, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro enzyme analysis showed mild reduction in enzyme activity (Lukas, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Jan 01, 2014)
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no assertion criteria provided
Method: research
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Fabry's disease
Affected status: unknown
Allele origin:
inherited
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Albrecht-Kossel-Institute, Medical University Rostock
Accession: SCV000246033.1
First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016 |
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drug response
Pharmacological Chaperone response: no
(Jan 01, 2014)
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no assertion criteria provided
Method: research
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deoxygalactonojirimycin response
Drug used for
Fabry disease
Affected status: unknown
Allele origin:
inherited
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Albrecht-Kossel-Institute, Medical University Rostock
Accession: SCV000246034.1
First in ClinVar: Mar 11, 2016 Last updated: Mar 11, 2016 |
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458762.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Accuracy diagnosis improvement of Fabry disease from dried blood spots: Enzyme activity, lyso-Gb3 accumulation and GLA gene sequencing. | Delarosa-Rodríguez R | Clinical genetics | 2021 | PMID: 33527381 |
Prevalence of Fabry disease in male dialysis patients: Argentinean screening study. | Frabasil J | JIMD reports | 2019 | PMID: 31392112 |
The New York pilot newborn screening program for lysosomal storage diseases: Report of the First 65,000 Infants. | Wasserstein MP | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30093709 |
Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. | Lin Y | Circulation. Cardiovascular genetics | 2017 | PMID: 29247119 |
Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease. | Lukas J | Human mutation | 2016 | PMID: 26415523 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
Text-mined citations for rs781838005 ...
HelpRecord last updated Jul 15, 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.