Submissions for variant NM_000169.3(GLA):c.680G>A (p.Arg227Gln)

dbSNP: rs104894840

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000157898	SCV000110134	pathogenic	not provided	2016-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000157898	SCV000207829	pathogenic	not provided	2024-08-13	criteria provided, single submitter	clinical testing	The p.(R227Q) missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (PMID: 7504405, 23935525); Functional studies in HEK-293 cells found that p.(R227Q) is associated with 0% residual enzyme activity compared to wild-type (PMID: 21598360, 23935525); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 29132836, 26652600, 26047621, 27356758, 26691501, 28283366, 33204599, 26712400, 33437642, 20615758, 15713906, 10916280, 27657681, 19387866, 18698230, 17206462, 30159316, 31341885, 30571380, 32442237, 32432376, 31447099, 12920095, 32203225, 31878969, 31996269, 32023956, 7504405, 21598360, 23935525)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011478	SCV000695744	pathogenic	Fabry disease	2020-11-09	criteria provided, single submitter	clinical testing	Variant summary: GLA c.680G>A (p.Arg227Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183490 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with Fabry Disease (e.g. Morrone_2003, Eng_1993, Morier_2010). Several of these patients had classic Fabry phenotype. These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have greatly reduced enzymatic activity (Lukas_2013, Morrone_2003, Wu_2011). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011478	SCV000834471	pathogenic	Fabry disease	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 227 of the GLA protein (p.Arg227Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 10916280, 15713906, 17206462, 26652600). ClinVar contains an entry for this variant (Variation ID: 10732). 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: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000011478	SCV000967592	pathogenic	Fabry disease	2024-03-20	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Revvity Omics, Revvity	RCV000157898	SCV002024300	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011478	SCV002054418	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
3billion	RCV000011478	SCV004013711	pathogenic	Fabry disease		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18698230, 19387866, 21598360, 23935525, 27657681). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010732 / PMID: 7504405). A different missense change at the same codon (p.Arg227Pro) has been reported to be associated with GLA related disorder (ClinVar ID: VCV000217394 / PMID: 26415523). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV000157898	SCV004226708	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PS3, PS4_moderate
OMIM	RCV000011478	SCV000031710	pathogenic	Fabry disease	1993-12-01	no assertion criteria provided	literature only