Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000390750 | SCV000329683 | pathogenic | not provided | 2021-06-17 | criteria provided, single submitter | clinical testing | Published functional studies show that mice carrying the S63C variant develop neuropathy (Wrabetz et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 7506095, 16495463, 26310628, 20461396, 27535533, 11935267, 6099985) |
| Athena Diagnostics Inc | RCV000390750 | SCV000614101 | pathogenic | not provided | 2022-10-24 | criteria provided, single submitter | clinical testing | This variant has been identified in at least one individual with Dejerine-Sottas disease and appears to occur de novo in one individual. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 11935267, 16495463. The variant is located in a region that is considered important for protein function and/or structure. |
| Invitae | RCV000803240 | SCV000943102 | pathogenic | Charcot-Marie-Tooth disease, type I | 2019-11-18 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser63 amino acid residue in MPZ. Other variant that disrupt this residue have been observed in affected individuals (PMID: 22734905, 7693130, 12402337, 8835320), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies using transgenic mouse models have shown that this missense change [p.Ser63Cys] creates a packing defect in the myelin sheath that leads to hypomyelination and these mice develop tremor, ataxia, weakness and muscle atrophy of hind limbs recapitulating phenotypes observed in human neuromuscular disease (PMID: 16495463, 20937820). This variant has been observed to be de novo in an individual affected with Dejerine-Sottas syndrome (PMID: 7506095). ClinVar contains an entry for this variant (Variation ID: 14169). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 63 of the MPZ protein (p.Ser63Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. |
| OMIM | RCV000015232 | SCV000035491 | pathogenic | Dejerine-Sottas syndrome, autosomal dominant | 1993-11-01 | no assertion criteria provided | literature only | |
| Inherited Neuropathy Consortium | RCV000789439 | SCV000928795 | uncertain significance | Dejerine-Sottas disease | no assertion criteria provided | literature only |