ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.1081G>A (p.Gly361Arg)

dbSNP: rs28935494
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235836 SCV000292838 pathogenic not provided 2015-04-23 criteria provided, single submitter clinical testing The R361R missense mutation in the GLA gene has been reported previously in association with Fabry disease in patients with a classic Fabry phenotype and absent alpha-galactosidase A enzyme activity (Ashley et al., 2001; Davies et al., 1993). Approximately 60-70% of females with a single GLA variant have some disease manifestations, and 10% of these individuals present with a disease severity that is similar to that of affected males (Bennett et al., 2002).
CeGaT Center for Human Genetics Tuebingen RCV000235836 SCV005434074 pathogenic not provided 2024-10-01 criteria provided, single submitter clinical testing GLA: PS1, PM1, PM2, PM5, PS3:Supporting, PS4:Supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV005090190 SCV005840478 pathogenic Fabry disease 2024-02-13 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 361 of the GLA protein (p.Gly361Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 8395937, 23935525, 30477121). ClinVar contains an entry for this variant (Variation ID: 245750). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly361 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 8395937, 20022777, 30988410), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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