Submissions for variant NM_000487.6(ARSA):c.1114C>T (p.Arg372Trp)

dbSNP: rs74315476

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723522	SCV000110793	pathogenic	not provided	2013-06-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000078933	SCV000486167	likely pathogenic	Metachromatic leukodystrophy	2016-04-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000078933	SCV000915982	pathogenic	Metachromatic leukodystrophy	2017-09-01	criteria provided, single submitter	clinical testing	The ARSA c.1114C>T (p.Arg372Trp) missense variant has been reported in at least four studies and is found in four children with arylsulfatase A deficiency, or metachromatic leukodystrophy, including in three individuals in a homozygous state and in one individual in a compound heterozygous state (Heinisch et al. 1995; Bertelli et al. 2006; Grossi et al. 2008; Biffi et al. 2008). One of the homozygous individuals carried the variant on a complex allele with a second missense variant in cis (Grossi et al. 2008). The p.Arg372Trp variant was absent from 100 control alleles and is reported at a frequency of 0.000116 in the East Asian population of the Exome Aggregation Consortium. Expression analysis in COS-7 and BHK cells found the p.Arg372Trp variant to be associated with significantly reduced ARSA activity compared to wild type (Heinisch et al. 1995; Bertelli et al. 2006; Grossi et al. 2008; Biffi et al. 2008). In addition, expression analysis of the complex allele showed further reduction in activity in comparison to the p.Arg372Trp or the second missense variant individually (Grossi et al. 2008). Based on the collective evidence, the p.Arg372Trp variant is classified as pathogenic for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000078933	SCV001548175	pathogenic	Metachromatic leukodystrophy	2021-03-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000078933	SCV002018808	pathogenic	Metachromatic leukodystrophy	2020-12-04	criteria provided, single submitter	clinical testing
Invitae	RCV000078933	SCV002196773	pathogenic	Metachromatic leukodystrophy	2023-06-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 7825603, 12086582). 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. ClinVar contains an entry for this variant (Variation ID: 3081). This variant is also known as 1108C>T, Arg370Trp. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7825603, 16678723, 18786133). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs74315476, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 372 of the ARSA protein (p.Arg372Trp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078933	SCV002555710	pathogenic	Metachromatic leukodystrophy	2022-06-07	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.1114C>T (p.Arg372Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250080 control chromosomes. c.1114C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Biffi_2008, Heinisch_1995, Fumagalli_2021). 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. Six 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.
OMIM	RCV000003227	SCV000023385	pathogenic	Metachromatic leukodystrophy, severe	2018-11-07	no assertion criteria provided	literature only
Gelb Laboratory, University of Washington	RCV000078933	SCV005046791	not provided	Metachromatic leukodystrophy		no assertion provided	in vitro