Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000674168 | SCV000799456 | likely pathogenic | Metachromatic leukodystrophy | 2018-04-18 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000674168 | SCV001338124 | pathogenic | Metachromatic leukodystrophy | 2020-01-31 | criteria provided, single submitter | clinical testing | Variant summary: ARSA c.1344dupC (p.Gly449ArgfsX124) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2e-05 in 249430 control chromosomes. c.1344dupC has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (example, Wang_2007, Liaw_2015, Wang_2016, Li_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV000674168 | SCV002146478 | pathogenic | Metachromatic leukodystrophy | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change results in a frameshift in the ARSA gene (p.Gly449Argfs*124). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the ARSA protein and extend the protein by 62 additional amino acid residues. This variant is present in population databases (rs761555167, gnomAD 0.03%). This frameshift has been observed in individual(s) with metachromatic leukodystrophy (PMID: 17560502, 27374302). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1338dupC. ClinVar contains an entry for this variant (Variation ID: 557962). This variant results in an extension of the ARSA protein. Other variant(s) that result in a similarly extended protein product (p.Arg498Profs*7) have been determined to be pathogenic (PMID: 19021637, 26462614). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |