ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.736C>T (p.Arg246Cys) (rs74315470)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003219 SCV000220426 likely pathogenic Metachromatic leukodystrophy 2014-06-19 criteria provided, single submitter literature only
Invitae RCV000003219 SCV001222941 pathogenic Metachromatic leukodystrophy 2020-07-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 246 of the ARSA protein (p.Arg246Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs74315470, ExAC 0.003%). This variant has been observed in combination with another GENE variant in individuals affected with metachromatic leukodystrophy (PMID: 22993277, 24001781, 26462614, 28670130). This variant is also known as p.Arg244Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 3073). 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. This variant disrupts the p.Arg246 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9090526, 22993277, 25965562, 26462614). 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.
OMIM RCV000003219 SCV000023377 pathogenic Metachromatic leukodystrophy 2018-11-07 no assertion criteria provided literature only
Natera, Inc. RCV000003219 SCV001462384 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing

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