ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.346C>T (p.Arg116Ter) (rs761860059)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000364716 SCV000330912 pathogenic not provided 2016-01-19 criteria provided, single submitter clinical testing
Medical Molecular Genetics Department, National Research Center RCV000984243 SCV000999155 pathogenic Metachromatic leukodystrophy criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000984243 SCV001361598 pathogenic Metachromatic leukodystrophy 2019-11-18 criteria provided, single submitter clinical testing Variant summary: ARSA c.346C>T (p.Arg116X) 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 9.9e-06 in 201088 control chromosomes (gnomAD). c.346C>T has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (e.g. Hettiarachchi_2019, Lugowska_2009, Tan_2010). These data indicate that the variant is very likely to be associated with disease. Protein activity in patients with the variant was determined to be considerably reduced compared to normal controls (Lugowska_2009, Tan_2010). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000984243 SCV001391388 pathogenic Metachromatic leukodystrophy 2020-03-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg116*) 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: 19021637). This variant is also known as p.Arg114* in the literature. ClinVar contains an entry for this variant (Variation ID: 280950). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984243 SCV001132335 likely pathogenic Metachromatic leukodystrophy 2015-04-14 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000364716 SCV001800735 pathogenic not provided no assertion criteria provided clinical testing

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