Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000460553 | SCV000553810 | pathogenic | Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5 | 2017-04-05 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine with arginine at codon 896 of the KCNT1 protein (p.Met896Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNT1-related disease. However, family studies have indicated that this variant was not present in the parents of an individual with KCNT1-related disease, which suggests that it was de novo in that affected individual (Invitae). This variant occurs  in the intracellular C-terminal region within a putative nicotinamide adeninedinucleotide (NAD+)-binding site (PMID: 19386908). A different missense substitution at this codon (p.Met896Ile) has been determined to be pathogenic (PMID: 23086396, 25482562, 24591078). In addition, a third variant (p.Met896Lys) has been reported de novo in an individual affected with early infantile epileptic encephalopathy (PMID:26993267). This suggests that the methionine residue is critical for KCNT1 protein function. For these reasons, this variant has been classified as Pathogenic. |