ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.302G>A (p.Gly101Asp) (rs74315455)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020318 SCV000221108 pathogenic Metachromatic leukodystrophy 2015-02-03 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724149 SCV000700718 likely pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020318 SCV000918484 pathogenic Metachromatic leukodystrophy 2018-06-25 criteria provided, single submitter clinical testing Variant summary: ARSA c.302G>A (p.Gly101Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 47324 control chromosomes (gnomAD). The variant, c.302G>A, has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Kondo_1991, Han_2015, Kurosawa_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kondo_1991). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000020318 SCV001404554 pathogenic Metachromatic leukodystrophy 2020-07-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 101 of the ARSA protein (p.Gly101Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs74315455, ExAC 0.07%). This variant has been observed in individual(s) with clinical features of metachromatic leukodystrophy (PMID: 1673291, 26131420, 20890085). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3053). This variant has been reported to affect ARSA protein function (PMID: 1673291). This variant disrupts the p.Gly101 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30057904, 26553228, 27779215, 27374302, 10477432). 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 RCV000003198 SCV000023356 pathogenic Metachromatic leukodystrophy, adult type 1991-05-01 no assertion criteria provided literature only
GeneReviews RCV000020318 SCV000040693 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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