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NM_000169.3(GLA):c.1088G>A (p.Arg363His)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
10 (Most recent: Nov 19, 2021)
Last evaluated:
Nov 20, 2020
Accession:
VCV000222141.8
Variation ID:
222141
Description:
single nucleotide variant
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NM_000169.3(GLA):c.1088G>A (p.Arg363His)

Allele ID
223822
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
Xq22.1
Genomic location
X: 101398011 (GRCh38) GRCh38 UCSC
X: 100652999 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_000169.2(GLA):c.1088G>A
NC_000023.10:g.100652999C>T
NC_000023.11:g.101398011C>T
... more HGVS
Protein change
R363H
Other names
-
Canonical SPDI
NC_000023.11:101398010:C:T
Functional consequence
effect on protein activity [Variation Ontology VariO:0053]
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD) 0.00013
Exome Aggregation Consortium (ExAC) 0.00003
Links
ClinGen: CA029545
UniProtKB: P06280#VAR_012435
dbSNP: rs111422676
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 7 criteria provided, multiple submitters, no conflicts Nov 20, 2020 RCV000398396.8
Pathogenic 3 criteria provided, single submitter May 1, 2018 RCV000724675.3
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
GLA Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
29 898
RPL36A-HNRNPH2 - - - GRCh38
GRCh37
- 889

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Jul 05, 2017)
criteria provided, single submitter
Method: clinical testing
Angiokeratoma corporis diffusum
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695730.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (7)
Comment:
Variant summary: The GLA c.1088G>A (p.Arg363His) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a damaging outcome for this variant. … (more)
Pathogenic
(May 01, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000331853.4
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (4)
Other databases
http://www.egl-eurofins.com/emvc…
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Angiokeratoma corporis diffusum
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893811.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Oct 10, 2018)
criteria provided, single submitter
Method: research
Angiokeratoma corporis diffusum
Allele origin: unknown
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993560.1
Submitted: (Aug 02, 2019)
Evidence details
Pathogenic
(Nov 20, 2020)
criteria provided, single submitter
Method: clinical testing
Angiokeratoma corporis diffusum
Allele origin: unknown
Baylor Genetics
Accession: SCV001522947.1
Submitted: (Feb 21, 2021)
Evidence details
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic
(Sep 03, 2020)
criteria provided, single submitter
Method: clinical testing
Angiokeratoma corporis diffusum
Allele origin: germline
Invitae
Accession: SCV001588429.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (7)
Comment:
This sequence change replaces arginine with histidine at codon 363 of the GLA protein (p.Arg363His). The arginine residue is moderately conserved and there is a … (more)
Pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Angiokeratoma corporis diffusum
(X-linked inheritance)
Allele origin: germline
Neuberg Supratech Reference Laboratories Pvt Ltd,Neuberg Centre for Genomic Medicine
Accession: SCV001712060.1
Submitted: (Jun 02, 2021)
Evidence details
Publications
PubMed (6)
Comment:
The missense variant p.R363H in GLA (NM_000169.2) has been reported previously in affected individuals with late onset Fabry disease (Blaydon et al 2001; Serebrinsky et … (more)
Uncertain significance
(Sep 16, 2018)
no assertion criteria provided
Method: research
not provided
Allele origin: germline
Gharavi Laboratory,Columbia University
Accession: SCV000920679.1
Submitted: (Mar 05, 2019)
Evidence details
Likely pathogenic
(Jan 22, 2020)
no assertion criteria provided
Method: curation
Angiokeratoma corporis diffusum
(X-linked inheritance)
Allele origin: germline
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001422922.1
Submitted: (Mar 09, 2020)
Comment:
X-linked inheritance (primarily recessive with milder female expression)
Evidence details
Publications
PubMed (1)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The p.Arg363His variant in GLA has been reported in at least eight individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345), segregated … (more)
Pathogenic
(Aug 14, 2020)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
PerkinElmer Genomics
Accession: SCV002024303.1
Submitted: (Nov 19, 2021)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Use of a rare disease registry for establishing phenotypic classification of previously unassigned <i>GLA</i> variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup. Germain DP Journal of medical genetics 2020 PMID: 32161151
Fabry disease and incidence of cancer. Bird S Orphanet journal of rare diseases 2017 PMID: 28877708
Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system. Navarrete-Martínez JI Molecular genetics and metabolism 2017 PMID: 28302345
Late onset variants in Fabry disease: Results in high risk population screenings in Argentina. Serebrinsky G Molecular genetics and metabolism reports 2015 PMID: 26937405
Exocrine pancreatic insufficiency is not a cause of abdominal complaints in patients with Fabry disease. Vujasinovic M Wiener klinische Wochenschrift 2015 PMID: 25835592
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Molecular damage in Fabry disease: characterization and prediction of alpha-galactosidase A pathological mutations. Riera C Proteins 2015 PMID: 25382311
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
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
The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines. Benjamin ER Journal of inherited metabolic disease 2009 PMID: 19387866
Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype. Shabbeer J Molecular genetics and metabolism 2002 PMID: 12175777
Fabry disease: 20 novel GLA mutations in 35 families. Blaydon D Human mutation 2001 PMID: 11668641
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0d919f76-589c-4982-a478-bfa07e747523 - - - -

Text-mined citations for rs111422676...

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These 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 Nov 28, 2021