Submissions for variant NM_000487.6(ARSA):c.302G>A (p.Gly101Asp)

dbSNP: rs74315455

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000020318	SCV000221108	pathogenic	Metachromatic leukodystrophy	2015-02-03	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724149	SCV000700718	likely pathogenic	not provided	2016-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020318	SCV000918484	pathogenic	Metachromatic leukodystrophy	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.302G>A (p.Gly101Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) of 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 4.2e-05 in 47324 control chromosomes (gnomAD). The variant, c.302G>A, has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Kondo_1991, Han_2015, Kurosawa_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kondo_1991). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000020318	SCV001404554	pathogenic	Metachromatic leukodystrophy	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 101 of the ARSA protein (p.Gly101Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 1673291, 20890085, 26131420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3053). 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: 1673291). This variant disrupts the p.Gly101 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10477432, 26553228, 27374302, 27779215, 30057904). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000724149	SCV004033962	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ARSA: PM1, PM2, PM3, PM5, PP4, PS3:Supporting
OMIM	RCV000003198	SCV000023356	pathogenic	Metachromatic leukodystrophy, adult type	1991-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000020318	SCV000040693	not provided	Metachromatic leukodystrophy		no assertion provided	literature only
Natera, Inc.	RCV000020318	SCV002083903	pathogenic	Metachromatic leukodystrophy	2021-03-24	no assertion criteria provided	clinical testing