ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.902G>A (p.Arg301Gln) (rs104894828)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723405 SCV000110142 pathogenic not provided 2017-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000244581 SCV000318975 pathogenic Cardiovascular phenotype 2013-10-22 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000011462 SCV000543766 pathogenic Fabry disease 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 301 of the GLA protein (p.Arg301Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs104894828, ExAC no frequency). This variant has been reported in multiple individuals affected with classic and atypical Fabry disease with evidence of co-segregation with disease in families (PMID: 23378663, 11688386, 15702404, 8738659, 2171331, 20505683, Invitae). ClinVar contains an entry for this variant (Variation ID: 10715). Experimental studies have shown that this variant causes a reduction in the GLA enzyme activity (PMID: 22241068, 9395081, 21598360). A different missense substitution at this codon (p.Arg301Pro) has been reported in an individual affected with Fabry disease (PMID: 11322659 ). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000011462 SCV000731639 pathogenic Fabry disease 2017-05-15 criteria provided, single submitter clinical testing The p.Arg301Gln variant in GLA has been reported in at least 10 individuals with Fabry disease (Sakuraba 1990, Sawada 1996, Germain 1999, Ashton-Prolla 2000, Ge rmain 2002, Mills 2005, Lee 2010, Brady 2015, Pan 2016, Lenders 2016, Ayako 2017 ) and segregated with disease in 7 affected relatives from 3 families (Brady 201 5, Pan 2016, Saito 2017). It was absent from large population studies. Functiona l assays showed decreased alpha-Gal activity, consistent with classic Fabry dise ase (Shin 2007, Brady 2015, Pan 2016, Saito 2017). In summary, this variant meet s criteria to be classified as pathogenic for Fabry disease based upon segregati on studies, absence from controls, and functional evidence.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845380 SCV000987439 pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
OMIM RCV000011461 SCV000031693 pathogenic Fabry disease, cardiac variant 2000-06-15 no assertion criteria provided literature only
OMIM RCV000011462 SCV000031694 pathogenic Fabry disease 2000-06-15 no assertion criteria provided literature only

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