Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169355 | SCV000220726 | likely pathogenic | Metachromatic leukodystrophy | 2014-09-23 | criteria provided, single submitter | literature only | |
| Invitae | RCV000169355 | SCV000752525 | pathogenic | Metachromatic leukodystrophy | 2023-04-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188976). This variant is also known as c.234dupC. This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 17438611). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs786204599, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.Gly81Argfs*53) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169355 | SCV001360438 | pathogenic | Metachromatic leukodystrophy | 2022-01-31 | criteria provided, single submitter | clinical testing | Variant summary: ARSA c.240dupC (p.Gly81ArgfsX53) 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 4.3e-06 in 232650 control chromosomes. c.240dupC has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Waye_2007, Calbi_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Calbi_2018). 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |