Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001062955 | SCV001227781 | likely pathogenic | Metachromatic leukodystrophy | 2022-04-18 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with metachromatic leukodystrophy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 148 of the ARSA protein (p.Gly148Ser). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 857311). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |