Submissions for variant NM_000169.3(GLA):c.668G>A (p.Cys223Tyr)

dbSNP: rs869312382

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194309	SCV001363736	pathogenic	Fabry disease	2020-11-06	criteria provided, single submitter	clinical testing	Variant summary: GLA c.668G>A (p.Cys223Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Cys223 is a residue known to form disulfide bonds that are essential for maintaining the correct structure of the active site (Schafer_2005).The variant was absent in 183422 control chromosomes (gnomAD). c.668G>A has been reported in the literature in multiple individuals affected with Fabry Disease (Schafer_2005, Boyd_2013, Cheung_2012, Limgala_2019, Sadick_2007, Shabbeer_2002). These data indicate that the variant is very likely to be associated with disease. Other variants at this same codon have been reported in associated with Fabry disease via HGMD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001781620	SCV002018446	likely pathogenic	not provided	2019-08-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001194309	SCV002243735	pathogenic	Fabry disease	2021-04-16	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 223 of the GLA protein (p.Cys223Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 12175777, 23430946, 15713906). ClinVar contains an entry for this variant (Variation ID: 222364). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Cys223 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 27560961, 29326878, 30386727, 10208848), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002363038	SCV002665360	likely pathogenic	Cardiovascular phenotype	2018-01-03	criteria provided, single submitter	clinical testing	The p.C223Y variant (also known as c.668G>A), located in coding exon 5 of the GLA gene, results from a G to A substitution at nucleotide position 668. The cysteine at codon 223 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was detected in a study of families with Fabry disease; however clinical details were limited (Shabbeer J et al. Mol Genet Metab. 2002;76(1):23-30). This alteration has also been reported in a patient with left ventricular hypertrophy (Boyd AC et al. J Am Soc Echocardiogr, 2013 Dec;26:1415-23). In addition, other alterations affecting the same amino acid (p.C223G (c.667T>G) and p.C223R (c.667T>C)) have also been reported in association with Fabry disease (Germain DP et al. Biochem Biophys Res Commun. 1999;257(3):708-13; Shabbeer J et al. Mol Genet Metab. 2002;76(1):23-30). This amino 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.
Fulgent Genetics, Fulgent Genetics	RCV001194309	SCV002789489	pathogenic	Fabry disease	2022-02-27	criteria provided, single submitter	clinical testing