ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1898C>T (p.Ser633Leu) (rs377750450)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522716 SCV000621247 uncertain significance not provided 2017-09-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNT1 gene. The S633L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.The S633L variant is observed in 1/111088 (0.0009%) alleles from individuals of Europeanbackground (Lek et al., 2016). The S633L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. Additionally, 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. Therefore, based on the currently available information, it is unclear whether thisvariant is a pathogenic variant or a rare benign variant.
Invitae RCV000555376 SCV000652920 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2017-03-10 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 633 of the KCNT1 protein (p.Ser633Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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