Submissions for variant NM_000169.3(GLA):c.1087C>T (p.Arg363Cys)

gnomAD frequency: 0.00001  dbSNP: rs797044776

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179729	SCV000232023	pathogenic	not provided	2015-02-03	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249019	SCV001422923	likely pathogenic	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Arg363Cys variant in GLA has been reported in the literature in two males with classic Fabry, as well as in five individuals in ClinVar (PMID: 12175777, 21598360; ID:198401), and has been identified in 0.00244% (2/81841) of European (non-Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044776). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as pathogenic by EGL Genetic Diagnostics (VariationID:198401). In vitro functional studies provide some evidence that the p.Arg363Cys variant may slightly impact protein function (PMID: 21598360, 27744182, 19387866). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype that is consistent with disease (PMID: 12175777). One additional likely pathogenic variant, causing a different amino acid change at the same position, p.Arg363His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 28302345,12175777, 23935525, 26937405,11668641,25382311/Variation ID: 222141). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2_supporting, PS3_supporting, PS4_moderate, PP4, PM5_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249019	SCV001554529	likely pathogenic	Fabry disease	2022-07-01	criteria provided, single submitter	clinical testing	Variant summary: GLA c.1087C>T (p.Arg363Cys) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183376 control chromosomes (gnomAD). c.1087C>T has been reported in the literature in individuals affected with later onset or non-classic presentations of Fabry Disease (example, Balendran_2020, Mauhin_2020, Arends_2018) and as a variant causing classical Fabry disease (example, Shabbeer_2002, cited in Benjamin_2009). These data do not allow a firm conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (example, Wu_2011, Benjamin_2009). The most pronounced variant effect results in <10% of normal activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249019	SCV001575313	pathogenic	Fabry disease	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 363 of the GLA protein (p.Arg363Cys). This variant is present in population databases (rs797044776, gnomAD 0.002%). This missense change has been observed in individual(s) with features of Fabry disease (PMID: 12175777; Invitae). ClinVar contains an entry for this variant (Variation ID: 198401). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Arg363 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11668641, 12175777, 26937405, 28302345). 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.
Color Diagnostics, LLC DBA Color Health	RCV001249019	SCV001736310	likely pathogenic	Fabry disease	2021-07-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 363 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant leads to 7.5% residual GLA enzyme activity when expressed in HEK-293 cells (PMID: 21598360). This variant has been reported in individuals affected with Fabry disease (PMID: 12175777, 19387866, 28749998, 29661900, 32442237) and a female with left ventricular hypertrophy (PMID: 31987665). Cultured cells from an affected male showed 8% residual GLA enzyme activity (PMID: 19387866), and an affected female showed elevated lysoglobotriaosylceramide levels (PMID: 28749998). This variant has been reported in a newborn (PMID: 28615118) and in a 33-year-old asymptomatic female (PMID: 31117083). Both of them had reduced GLA enzyme activity. This variant has been identified in 2/183376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg363His, has been associated with Fabry disease (Clinvar variation ID: 222141), indicating that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000179729	SCV002024322	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001249019	SCV002054374	likely pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001249019	SCV002807958	likely pathogenic	Fabry disease	2021-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000179729	SCV003194980	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significantly reduced enzyme activity (Wu et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29437868, 31860127, 25382311, 22063097, 28615118, 12175777, 27657681, 32442237, 31987665, 21598360)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001249019	SCV001430847	likely pathogenic	Fabry disease	2019-06-27	no assertion criteria provided	research	GLA Arg353Cys has been previously identified in 5 Fabry patients (Phyu P, et al., 2018; Pettazzoni M, et al., 2017; Benjamin ER, et al., 2009; Shabbeer J, et al., 2002). We identified this variant in a patient presenting with left ventricular hypertrophy, subsequent clinical screening confirmed a diagnosis of Fabry disease. The variant is present at a low frequency in the Genome Aggregation Database (MAF= 0.000011 http://gnomad.broadinstitute.org/). In silico tools SIFT and PolyPhen-2 predict this variant to be benign, however MutationTaster predicts this variant to be "Disease causing". Interestingly another amino acid change at this position (Arg363His) has been classified as pathogenic. suggesting that an amino acid substitution at this site may not be tolerated. In summary, based on rarity in the general population, reports of this variant in affected individuals, and because Fabry disease is caused only by variants in the GLA gene, we classify GLA Arg353Cys as "likely pathogenic".