ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.901C>G (p.Arg301Gly) (rs398123224)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156338 SCV000206056 uncertain significance not specified 2014-02-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg301Gly v ariant in GLA has been listed in HGMD as reported in an individual with Fabry di sease, though that publication could not be found. Studies have shown that this variant leads to reduce, but residual GLA function (Lukas 2013); however, this i n vitro assay may not accurately represent biological function. This variant was absent from large population studies. Other missense variants at this position (Arg301Gln, Arg301Pro) have been reported in individuals with Fabry disease (Sak uraba 1990, Ashley 2001), suggesting that variation at this position may not be tolerated, though additional studies are needed. Computational prediction tools and conservation analysis suggest that the Arg301Gly variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . Although this data supports that this variant may be pathogenic, additional st udies are needed to fully assess its clinical significance.
Invitae RCV000823627 SCV000964492 pathogenic Fabry disease 2019-04-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 301 of the GLA protein (p.Arg301Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Fabry disease or clinical features of this condition (PMID: 12175777, 28672034, Invitae). ClinVar contains an entry for this variant (Variation ID: 179546). Experimental studies have shown that this missense change results in the reduced GLA enzyme activity (PMID: 23935525, 27657681). This variant disrupts the p.Arg301 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23378663, 11688386, 15702404, 8738659, 2171331, 20505683, 22241068, 9395081, 21598360), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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