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

dbSNP: rs397515870

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	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	RCV000723986	SCV003824065	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing