Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001037092 | SCV001200489 | pathogenic | Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 | 2022-03-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 SETX protein function. ClinVar contains an entry for this variant (Variation ID: 836058). This missense change has been observed in individual(s) with autosomal recessive spinocerebellar ataxia (PMID: 23566282). 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 present in population databases (rs753713810, gnomAD 0.006%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 274 of the SETX protein (p.Met274Val). |
| Athena Diagnostics Inc | RCV002473168 | SCV002771068 | uncertain significance | not provided | 2022-08-08 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003413819 | SCV004113632 | uncertain significance | SETX-related condition | 2022-10-26 | criteria provided, single submitter | clinical testing | The SETX c.820A>G variant is predicted to result in the amino acid substitution p.Met274Val. This variant has been reported in the compound heterozygous state in two siblings with autosomal recessive spinocerebellar ataxia with axonal neuropathy 2 (Datta et al 2013. PubMed ID: 23566282), and in the heterozygous state in a patient with amyotrophic lateral sclerosis (ALS), where it was predicted to act in an oligogenic manner with other rare variants in ALS associated genes (Cady J et al 2014. PubMed ID: 25382069). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-135210013-T-C). Although we suspect that this variant may be pathogenic for autosomal recessive SETX-associated disorders, at this time, the clinical significance of this variant is uncertain due to insufficient conclusive functional and genetic evidence. |