ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.937C>T (p.Arg313Ter) (rs551472773)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000501028 SCV000593421 pathogenic Metachromatic leukodystrophy 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000760416 SCV000890294 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The R313X variant has previously been reported as R311X in unrelated individuals with metachromatic leukodystrophy (MLD) who were homozygous for R313X or heterozygous for R313X and another pathogenic variant in the ARSA gene (Rafi et al., 2003; Luzi et al., 2013). The R313X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret R313X to be a pathogenic variant.
Invitae RCV000501028 SCV001221514 pathogenic Metachromatic leukodystrophy 2020-10-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg313*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with metachromatic leukodystrophy (PMID: 12809637). This variant is also known as p.Arg311* in the literature. ClinVar contains an entry for this variant (Variation ID: 434394). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501028 SCV001361599 pathogenic Metachromatic leukodystrophy 2019-11-11 criteria provided, single submitter clinical testing Variant summary: ARSA c.937C>T (p.Arg313X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 242628 control chromosomes (gnomAD). c.937C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Metachromatic Leukodystrophy (Rafi_2003, Luzi_2013). These data indicate that the variant is likely to be associated with disease. These publications also reported decreased enzyme activity and elevated urinary sulfatide excretion in the patients carrying the variant (Rafi_2003, Luzi_2013). Two ClinVar submissions (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 RCV000501028 SCV001369703 pathogenic Metachromatic leukodystrophy 2018-10-03 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Counsyl RCV000501028 SCV001132333 likely pathogenic Metachromatic leukodystrophy 2014-01-02 no assertion criteria provided clinical testing

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