Submissions for variant NM_000169.3(GLA):c.713G>A (p.Ser238Asn)

dbSNP: rs730880450

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157899	SCV000207830	pathogenic	not provided	2012-12-10	criteria provided, single submitter	clinical testing	The Ser238Asn mutation in the GLA gene has been reported in two unrelated males with late onset HCM and low plasma galactosidase A activity (Monserrat L et al., 2007). Mutations in nearby residues (Trp236Arg, Trp236Cys, Trp236Leu, Ile239Thr, Ile242Thr) have been reported in association with Fabry disease, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ser238Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000157899	SCV000281230	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781420	SCV000919438	pathogenic	Fabry disease	2020-08-18	criteria provided, single submitter	clinical testing	Variant summary: GLA c.713G>A (p.Ser238Asn) 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 183483 control chromosomes. c.713G>A has been reported in the literature in individuals with phenotypes ranging from classic Fabry disease (Vieitez_2018) to seemingly isolated GLA-HCM (Monserrat_2007), to late-onset Fabry disease, which may be related to skewed X-inactivation with predominant expression of the wild-type GLA allele (Echevarria_2015). In vitro enzyme activity was shown to be 36% of wild-type (Lukas_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000781420	SCV002054416	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Invitae	RCV000781420	SCV002177529	pathogenic	Fabry disease	2023-07-25	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 238 of the GLA protein (p.Ser238Asn). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). 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 not expected to disrupt GLA protein function. ClinVar contains an entry for this variant (Variation ID: 180841). This missense change has been observed in individual(s) with Fabry disease (PMID: 18154965). It has also been observed to segregate with disease in related individuals.
Ambry Genetics	RCV002362843	SCV002665491	likely pathogenic	Cardiovascular phenotype	2020-12-18	criteria provided, single submitter	clinical testing	The p.S238N variant (also known as c.713G>A), located in coding exon 5 of the GLA gene, results from a G to A substitution at nucleotide position 713. The serine at codon 238 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in Fabry disease and hypertrophic cardiomyopathy cohorts, and appeared to segregate with disease in one family (Monserrat L et al. J Am Coll Cardiol, 2007 Dec;50:2399-403; Echevarria L et al. Clin Genet, 2016 Jan;89:44-54; Jain R et al. JACC Cardiovasc Imaging, 2018 Apr;11:644-647; Vieitez I et al. Orphanet J Rare Dis, 2018 04;13:52; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948). In vitro functional studies showed this variant with approximately 37% of wild-type alpha-galactosidase A activity (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Nowak A et al. J Inherit Metab Dis, 2020 03;43:326-333). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000157899	SCV003828221	likely pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing