ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1174C>T (p.Arg392Trp) (rs74315480)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003231 SCV000221075 likely pathogenic Metachromatic leukodystrophy 2015-01-23 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723375 SCV000330911 uncertain significance not provided 2016-05-23 criteria provided, single submitter clinical testing
Invitae RCV000003231 SCV001211372 pathogenic Metachromatic leukodystrophy 2020-03-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 392 of the ARSA protein (p.Arg392Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs74315480, ExAC 0.006%). This variant has been observed to segregate with metachromatic leukodystrophy in a family (PMID: 21167507), and has also been observed in individuals with metachromatic leukodystrophy (PMID: 26462614, 26553228). This variant is also known as p.Arg390Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 3085). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg392 amino acid residue in ARSA. Another variant that disrupts this residue has been observed in individuals with ARSA-related conditions (PMID: 9452102, 26462614, 20339381), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003231 SCV000023389 pathogenic Metachromatic leukodystrophy 2018-11-07 no assertion criteria provided literature only
Natera, Inc. RCV000003231 SCV001462378 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing

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