ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.613C>A (p.Pro205Thr)

dbSNP: rs397515870
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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 RCV000153322 SCV000058953 likely pathogenic Fabry disease 2016-06-07 criteria provided, single submitter clinical testing The p.Pro205Thr variant in GLA has been reported in at least 4 individuals with Fabry disease and/or LVH (Blanch 1996, Davies 1996, Schafer 2005, Shimotori 2008 ) and has been identified by our laboratory in 1 family with HCM, segregating wi th one affected relative. It was absent from large population studies. In vitro assays showed the p.Pro205Thr variant was associated with decreased alpha-Gal ac tivity (~18% of normal enzyme activity), and that enzymatic levels increased aft er treatment with an experimental chaperone (Shimotori 2008, Wu 2011). However, these in vitro assays may not accurately represent biological function. In summa ry, this variant is likely to be pathogenic, though additional studies are requi red to fully establish its clinical significance.
Eurofins Ntd Llc (ga) RCV000723986 SCV000202802 pathogenic not provided 2017-09-27 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769540 SCV000900935 likely pathogenic Cardiomyopathy 2017-05-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000153322 SCV002054428 likely pathogenic Fabry disease 2021-07-15 criteria provided, single submitter clinical testing
Invitae RCV000153322 SCV002179136 pathogenic Fabry disease 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 205 of the GLA protein (p.Pro205Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical feature of Fabry disease (PMID: 8875188, 15776423, 18205205, 25611685, 27532257, 32150461). ClinVar contains an entry for this variant (Variation ID: 42456). 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 expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 18205205, 21598360). This variant disrupts the p.Pro205 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 8807334, 12175777, 15776423, 28728877), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002354187 SCV002657033 likely pathogenic Cardiovascular phenotype 2019-10-23 criteria provided, single submitter clinical testing The p.P205T variant (also known as c.613C>A), located in coding exon 4 of the GLA gene, results from a C to A substitution at nucleotide position 613. The proline at codon 205 is replaced by threonine, an amino acid with highly similar properties. This alteration has been detected in two individuals with Fabry disease; however, specific phenotypic information, including alpha-galactosidase A (α-Gal A) enzymatic levels, were not provided (Blanch LC et al. Hum. Mutat., 1996;8:38-43; Shimotori M et al. Hum. Mutat., 2008 Feb;29:331). In addition, this alteration has been detected in individuals with hypertrophic and dilated cardiomyopathies (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). Functional studies showed that this alteration is associated with 18% α-Gal A enzyome activity compared to wild type (Wu X et al. Hum. Mutat., 2011 Aug;32:965-77). A different alteration located at the same position, p.P205S, has been detected in two individuals with Fabry disease (Pan X et al. PLoS ONE, 2016 Aug;11:e0161330; Nowak A et al. Mol. Genet. Metab., 2018 02;123:148-153). The p.P205T acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity Omics RCV000723986 SCV003824065 pathogenic not provided 2022-05-31 criteria provided, single submitter clinical testing

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