Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002230093 | SCV000550573 | likely pathogenic | Hereditary spastic paraplegia 8; Ritscher-Schinzel syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 696 of the KIAA0196 protein (p.Gly696Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (Invitae). ClinVar contains an entry for this variant (Variation ID: 410079). 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 KIAA0196 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly696 amino acid residue in KIAA0196. Other variant(s) that disrupt this residue have been observed in individuals with KIAA0196-related conditions (PMID: 23455931; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. |
| Paris Brain Institute, |
RCV001391386 | SCV001451201 | pathogenic | Hereditary spastic paraplegia 8 | criteria provided, single submitter | clinical testing | ||
| Gene |
RCV000490087 | SCV000576857 | uncertain significance | not provided | 2017-04-17 | flagged submission | clinical testing | A variant of uncertain significance has been identified in the KIAA0196 gene. The G696S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G696S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G696S 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant at the same residues (G696A) has been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014). However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |