ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.868C>T (p.Arg290Cys) (rs74315473)

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Total submissions: 3
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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
Invitae RCV000003223 SCV000816680 pathogenic Metachromatic leukodystrophy 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 290 of the ARSA protein (p.Arg290Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs74315473, ExAC 0.009%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with metachromatic leukodystrophy and combined with other rare ARSA variants in several individuals affected with the same condition (PMID: 7866401, 16678723, 17560502, 19815439, 26462614). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Arg288Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 3077). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg290 amino acid residue in ARSA have been observed in affected individuals (PMID: 10477432, 12809637, 26462614, 24001781, 16678723). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003223 SCV000023381 pathogenic Metachromatic leukodystrophy 2018-11-07 no assertion criteria provided literature only

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