ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.847G>T (p.Asp283Tyr) (rs199476386)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000058982 SCV000110814 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing
Counsyl RCV000668155 SCV000792709 uncertain significance Metachromatic leukodystrophy 2017-07-20 criteria provided, single submitter clinical testing
Invitae RCV000668155 SCV001226680 pathogenic Metachromatic leukodystrophy 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 283 of the ARSA protein (p.Asp283Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with metachromatic leukodystrophy (PMID: 10533072). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also referred to p.Asp281Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 68151). 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.Asp283 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 28670130, 30057904, 31694723), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
UniProtKB/Swiss-Prot RCV000058982 SCV000090503 not provided not provided no assertion provided not provided

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