ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.1066C>T (p.Arg356Trp)

dbSNP: rs104894827
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000011459 SCV000058947 pathogenic Fabry disease 2018-09-26 criteria provided, single submitter clinical testing The Arg356Trp variant in GLA has been reported in at least 10 individuals with F abry disease or hypertrophic cardiomyopathy, including at least 2 females, and s egregated with disease in 4 clinically or biochemically affected family members across 3 families most of whom had a "mild classic" Fabry disease phenotype (Ber nstein 1989, Lin 2009, Turaca 2012, Romao 2013, Pasqualim 2014, LMM data). This variant was absent from large population studies. Several in vitro functional st udies have shown that this variant is associated with significantly reduced alph a-galactosidase A activity (Wu 2011, Siekierska 2012, Lukas 2013). In summary, t his variant meets criteria to be classified as pathogenic for X-linked Fabry dis ease based on case observations, segregation studies, absence from controls, and functional evidence. ACMG/AMP criteria applied: PS4, PM2, PS3_Moderate, PP1, PP 4.
Labcorp Genetics (formerly Invitae), Labcorp RCV000011459 SCV001579967 pathogenic Fabry disease 2023-07-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 356 of the GLA protein (p.Arg356Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 2539398, 23537685). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10713). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 17555407, 23935525). This variant disrupts the p.Arg356 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19621417, 27238910, 28615118). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001781217 SCV002024278 pathogenic not provided 2019-10-28 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000011459 SCV002054377 pathogenic Fabry disease 2021-07-15 criteria provided, single submitter clinical testing
GeneDx RCV001781217 SCV004039864 pathogenic not provided 2023-04-03 criteria provided, single submitter clinical testing Published functional studies demonstrate a severe reduction in enzyme activity (Ishii et al., 2007; Wu et al., 2011; Siekierska et al. 2012; Lukas et al., 2013; Germain et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23537685, 25382311, 27532257, 30477121, 17555407, 17532296, 23935525, 24582695, 25611685, 24334114, 32843101, 30879055, 22551898, 21598360, 22773828, 31996269, Neves2020[Article], 19521690, 18633574, 32023956, 24613481, 27916943, 29305833, 33163363, 19156839, 29935990, 20031620, 28615118, 17894781, 32647377, 27825144, 22063097, 18698230, 19387866, Rubino2022[CaseReport], 2539398, 30723321)
PreventionGenetics, part of Exact Sciences RCV003398483 SCV004120579 pathogenic GLA-related disorder 2023-06-09 criteria provided, single submitter clinical testing The GLA c.1066C>T variant is predicted to result in the amino acid substitution p.Arg356Trp. This variant has been reported in individuals with Fabry disease (Bernstein et al. 1989. PubMed ID: 2539398; Romão et al. 2013. PubMed ID: 23537685). Functional studies indicate this variant impacts protein solubility, aggregation, and activity (Siekierska et al. 2012. PubMed ID: 22773828; Table S1, Lukas. 2013. PubMed ID: 23935525; Wu et al. 2011. PubMed ID: 21598360). Different missense variants impacting the same amino acid residue (p.Arg356Gln, p.Arg356Pro) have also been reported in individuals with Fabry disease phenotypes or have been shown to impact GLA activity (Hwu et al. 2009. PubMed ID: 19621417; Lukas et al. 2016. PubMed ID: 26415523). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM RCV000011459 SCV000031691 pathogenic Fabry disease 1989-04-01 no assertion criteria provided literature only

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