Submissions for variant NM_000487.6(ARSA):c.370G>A (p.Gly124Ser)

gnomAD frequency: 0.00001  dbSNP: rs74315461

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078945	SCV000110806	uncertain significance	not provided	2016-10-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623394	SCV000742234	pathogenic	Inborn genetic diseases	2017-01-31	criteria provided, single submitter	clinical testing
Invitae	RCV000003209	SCV001559456	likely pathogenic	Metachromatic leukodystrophy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 124 of the ARSA protein (p.Gly124Ser). This variant is present in population databases (rs74315461, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ARSA-related conditions (PMID: 7902317, 7981715, 31130284). This variant is also known as c.364G>A (p.Gly122Ser). ClinVar contains an entry for this variant (Variation ID: 3063). 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 ARSA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 7902317). This variant disrupts the p.Gly124 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19021637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003209	SCV003934534	likely pathogenic	Metachromatic leukodystrophy	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.370G>A (p.Gly124Ser) 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. The variant allele was found at a frequency of 1.4e-05 in 216762 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.370G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy, including homozygous and compound heterozygous patients (e.g., Honke_1993, Kappler_1994, Wang_2016, Monies_2019, Hong_2020). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating absent protein product in an in vitro expression system (Honke_1993), and less than 1% of normal activity in patient derived cells (Hong_2020). In addition, other missense variants impacting the same codon (G124D/C), have been reported in association with Metachromatic leukodystrophy (HGMD). The following publications have been ascertained in the context of this evaluation (PMID: 31922725, 7902317, 7981715, 31130284, 27779215). Three ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: two submitters classified the variant as uncertain significance, and one submitter classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000003209	SCV004046860	pathogenic	Metachromatic leukodystrophy	2023-10-20	criteria provided, single submitter	clinical testing	Homozygous status for variant c.370G>A (p.Gly124Ser) in exon 2 of the ARSB gene. This variant has not been reported in 1000 genomes and has MAF of 0.0014% in gnomAD databases. The in-silico prediction of the variant is deleterious by SIFT, Mutation Taster, FATHM and DANN. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415633	SCV004115599	likely pathogenic	ARSA-related disorder	2023-02-20	criteria provided, single submitter	clinical testing	The ARSA c.370G>A variant is predicted to result in the amino acid substitution p.Gly124Ser. This variant has been reported in the homozygous, compound heterozygous, and heterozygous states (with no second variant found) in individuals with autosomal recessive metachromatic leukodystrophy (Kappler et al. 1994. PubMed ID: 7981715; Monies et al. 2019. PubMed ID: 31130284; Hou et al. 2020. PubMed ID: 31980526; Honke et al. 1993. PubMed ID: 7902317). Functional studies support its pathogenicity (Honke et al. 1993. PubMed ID: 7902317). This variant is reported in 0.0063% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-51065689-C-T). We classify this variant as likely pathogenic.
OMIM	RCV000003209	SCV000023367	pathogenic	Metachromatic leukodystrophy	1994-01-01	no assertion criteria provided	literature only
Gelb Laboratory, University of Washington	RCV000003209	SCV005046649	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro