Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000418994 | SCV000534817 | likely pathogenic | not provided | 2016-12-09 | criteria provided, single submitter | clinical testing | A published N107K variant that is likely pathogenic has been identified in the TBC1D24 gene. The N107K variant has been reported previously in two unrelated Navajo individuals with refractory epilepsy, developmental delays, and head growth deceleration who also had a second TBC1D24 variant identified on the opposite allele (Appavu et al., 2016). The N107K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N107K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, Lysine is observed at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV001049900 | SCV001213974 | likely pathogenic | Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 | 2023-06-10 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 107 of the TBC1D24 protein (p.Asn107Lys). This variant is not present in population databases (gnomAD no frequency). 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. 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 not expected to disrupt TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 391688). This missense change has been observed in individual(s) with autosomal recessive TBC1D24-related epilepsy (PMID: 27502353). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. |