Submissions for variant NM_000169.3(GLA):c.659G>A (p.Arg220Gln)

gnomAD frequency: 0.00001  dbSNP: rs869312378

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187255	SCV001353992	uncertain significance	Fabry disease	2024-08-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 220 of the GLA protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. Experimental functional studies in vitro have shown that this variant does not cause a decrease in GLA enzyme activity (PMID: 23935525, 31036492). This variant has been reported in an individual suspected to be affected with Fabry disease (PMID: 31996269), in three individuals affected with kidney disease (PMID: 36564230), in an infant affected with low GLA enzyme activity as determined by blood spot test during newborn screening (PMID: 23465405), and in an individual with cardiological symptoms of unexplained etiology (PMID: 23935525). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001187255	SCV001502682	uncertain significance	Fabry disease	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 220 of the GLA protein (p.Arg220Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 23935525; Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine 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 does not substantially affect GLA function (PMID: 23935525). This variant disrupts the p.Arg220 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 23608164), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001187255	SCV001822171	uncertain significance	Fabry disease	2021-07-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001187255	SCV002815953	uncertain significance	Fabry disease	2022-02-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150098	SCV003838837	uncertain significance	Cardiomyopathy	2021-10-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001187255	SCV002081342	uncertain significance	Fabry disease	2021-06-10	no assertion criteria provided	clinical testing