ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.868C>T (p.Arg290Cys)

gnomAD frequency: 0.00001  dbSNP: rs74315473
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003223 SCV000485475 likely pathogenic Metachromatic leukodystrophy 2015-12-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000003223 SCV000816680 pathogenic Metachromatic leukodystrophy 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 290 of the ARSA protein (p.Arg290Cys). 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 ARSA-related conditions (PMID: 7866401, 16678723, 17560502, 19815439, 26462614). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg288Cys. ClinVar contains an entry for this variant (Variation ID: 3077). 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%. This variant disrupts the p.Arg290 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 10477432, 12809637, 16678723, 24001781, 26462614), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV001642197 SCV001519295 pathogenic Spastic ataxia 2021-07-12 criteria provided, single submitter research
Fulgent Genetics, Fulgent Genetics RCV000003223 SCV002776151 pathogenic Metachromatic leukodystrophy 2022-03-15 criteria provided, single submitter clinical testing
GeneDx RCV004819990 SCV005440752 pathogenic not provided 2024-06-26 criteria provided, single submitter clinical testing Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 37480112); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R288C; This variant is associated with the following publications: (PMID: 26462614, 7866401, 12809637, 24001781, 10477432, 34445196, 37480112, 19815439, 20339381, 16678723, 33855715, 17560502)
OMIM RCV000003223 SCV000023381 pathogenic Metachromatic leukodystrophy 2018-11-07 no assertion criteria provided literature only
Gelb Laboratory, University of Washington RCV000003223 SCV005046526 not provided Metachromatic leukodystrophy no assertion provided in vitro

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