ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.942G>T (p.Glu314Asp)

dbSNP: rs199476390
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001004415 SCV001163455 likely pathogenic Metachromatic leukodystrophy criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001004415 SCV002146359 uncertain significance Metachromatic leukodystrophy 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 314 of the ARSA protein (p.Glu314Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 10751093). This variant is also known as E312D. ClinVar contains an entry for this variant (Variation ID: 68166). 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. Experimental studies have shown that this missense change affects ARSA function (PMID: 10751093, 28762252). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001004415 SCV003844767 likely pathogenic Metachromatic leukodystrophy 2023-02-15 criteria provided, single submitter clinical testing Variant summary: ARSA c.942G>T (p.Glu314Asp) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 241008 control chromosomes (gnomAD). c.942G>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (ML) or features of ML (example: Bohringer_2017 and Herman_2000). These data do not allow any conclusion about variant significance. Multiple publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Bohringer_2017 and Herman_2000). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
UniProtKB/Swiss-Prot RCV000058998 SCV000090519 not provided not provided no assertion provided not provided

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