ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1264del (p.Ser421_Leu422insTer)

gnomAD frequency: 0.00003  dbSNP: rs755635209
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483720 SCV000574339 likely pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD)
Revvity Omics, Revvity RCV000673517 SCV003817384 likely pathogenic Metachromatic leukodystrophy 2022-11-30 criteria provided, single submitter clinical testing
Invitae RCV000673517 SCV004677688 pathogenic Metachromatic leukodystrophy 2023-05-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ARSA protein in which other variant(s) (p.Pro428Leu) have been determined to be pathogenic (PMID: 1670590, 9090526, 9096767, 11941485, 26462614). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 424522). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. This variant is present in population databases (rs755635209, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Leu422*) in the ARSA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the ARSA protein.
Counsyl RCV000673517 SCV000798728 likely pathogenic Metachromatic leukodystrophy 2018-03-22 no assertion criteria provided clinical testing

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