ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1420C>T (p.Arg474Cys) (rs866242631)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255800 SCV000321804 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing The R474C missense variant in the KCNT1 gene has been reported previously as a de novo change in two individuals with epilepsy of infancy with migrating focal seizures (EIMFS; also known as malignant migrating partial seizures in infancy) (Ohba et al., 2015, Shimada et al., 2014 ) The R474C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. 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. In addition, a missense variant at the same position (R474H) in a nearby residue (R477T) have been reported in the Human Gene Mutation Database in association with KCNT1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, R474C is interpreted as a pathogenic variant.
Invitae RCV000805872 SCV000945846 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 474 of the KCNT1 protein (p.Arg474Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals with early infantile epileptic encephalopathy (PMID: 26140313, 27081515, 27652284). It is also known as p.Arg429Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 265210). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg474 amino acid residue in KCNT1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23086397, 25482562, 27779742), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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