Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000538183 | SCV000652936 | pathogenic | Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 | 2017-09-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with leucine at codon 950 of the KCNT1 protein (p.Arg950Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNT1-related disease. However, family studies have indicated that this variant was not present in the parents of an individual with seizures, which suggests that it was de novo in that affected individual (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg950Gln) has been determined to be pathogenic (PMID: 26122718, 27029629). This suggests that the arginine residue is critical for KCNT1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |