ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1010A>T (p.Asp337Val) (rs74315475)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169024 SCV000220172 likely pathogenic Metachromatic leukodystrophy 2014-03-20 criteria provided, single submitter literature only
GeneDx RCV000413321 SCV000490408 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing The D337V variant has previously been reported as D335V in association with MLD (Gieselmann et al., 1994; Eng et al., 2003; Lugowska et al., 2010). Functional analysis of D337V found that it is associated with no detectable enzyme activity (Hess et al., 1996). Therefore, we interpret D337V to be a pathogenic variant.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414806 SCV000492921 pathogenic Leukodystrophy 2015-03-13 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000169024 SCV000593420 pathogenic Metachromatic leukodystrophy 2016-02-11 criteria provided, single submitter clinical testing
Invitae RCV000169024 SCV000836843 pathogenic Metachromatic leukodystrophy 2020-09-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 337 of the ARSA protein (p.Asp337Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs74315475, ExAC 0.008%). This variant has been reported as homozygous or in combination with another ARSA variant in individuals affected with metachromatic leukodystrophy (PMID: 8723680, 14517960, 10381328, 20339381, 7866401). It has also been reported to segregate with metachromatic leukodystrophy in multiple families (PMID: 14517960, 10381328). This variant is also known as Asp335Val in the literature. ClinVar contains an entry for this variant (Variation ID: 3080). Experimental studies have shown that this missense change results in an ARSA protein that is catalytically inactive (PMID: 8723680). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169024 SCV001163454 pathogenic Metachromatic leukodystrophy criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169024 SCV001360433 pathogenic Metachromatic leukodystrophy 2019-04-02 criteria provided, single submitter clinical testing Variant summary: ARSA c.1010A>T (p.Asp337Val) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain 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 3.9e-05 in 229750 control chromosomes (gnomAD). c.1010A>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Lugowska_2010, Eng_2003, Qu_1999, Hess_1996). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause a complete loss of catalytic activity of the enzyme (Hess_1996). Six ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000169024 SCV001369264 pathogenic Metachromatic leukodystrophy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
OMIM RCV000003226 SCV000023384 pathogenic Metachromatic leukodystrophy, severe 2018-11-07 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000413321 SCV000801467 pathogenic not provided 2018-02-07 no assertion criteria provided clinical testing
Natera, Inc. RCV000169024 SCV001462380 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing

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