ClinVar Miner

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

dbSNP: rs74315476
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Total submissions: 9
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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

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