ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.418dup (p.His140fs) (rs745884435)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598862 SCV000710122 pathogenic not provided 2017-11-17 criteria provided, single submitter clinical testing The c.418dupC pathogenic variant in the ARSA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant has been observed in a patient referred for genetic testing at GeneDx whose features are suggestive of metachromatic leukodystrophy. The c.418dupC variant causes a frameshift starting with codon Histidine 140, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 36 of the new reading frame, denoted p.His140ProfsX36. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.418dupC variant is observed in 7/8,684 (0.08%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). We interpret c.418dupC as a pathogenic variant.
Ambry Genetics RCV001265855 SCV001444027 pathogenic Inborn genetic diseases 2018-02-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409085 SCV001467974 pathogenic Metachromatic leukodystrophy 2020-12-22 criteria provided, single submitter clinical testing Variant summary: ARSA c.418dupC (p.His140ProfsX36) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.4e-05 in 239254 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ARSA causing Metachromatic Leukodystrophy (8.4e-05 vs 0.0028), allowing no conclusion about variant significance. c.418dupC has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (e.g. Marcao_1999, Eng_2003, Virgens_2015). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000409085 SCV001592678 pathogenic Metachromatic leukodystrophy 2020-09-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His140Profs*36) in the ARSA gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 10220151). ClinVar contains an entry for this variant (Variation ID: 370305). 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 RCV000409085 SCV000485574 likely pathogenic Metachromatic leukodystrophy 2016-09-09 no assertion criteria provided clinical testing
Natera, Inc. RCV000409085 SCV001452356 pathogenic Metachromatic leukodystrophy 2020-09-16 no assertion criteria provided clinical testing

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