ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.2687T>G (p.Met896Arg) (rs1060503696)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460553 SCV000553810 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 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.

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