Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000213985 | SCV000279875 | uncertain significance | not provided | 2018-07-03 | criteria provided, single submitter | clinical testing | The L631S variant in the ATP7A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L631S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L631S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E628V, A629P, K633R, D635H) have been reported in the Human Gene Mutation Database in association with Menkes syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L631S as a variant of uncertain significance. |
| Invitae | RCV001854757 | SCV002152242 | uncertain significance | Menkes kinky-hair syndrome; Cutis laxa, X-linked; X-linked distal spinal muscular atrophy type 3 | 2022-07-26 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 631 of the ATP7A protein (p.Leu631Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATP7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 234827). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |