ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.1612C>T (p.Arg538Cys) (rs774588571)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000429853 SCV000532946 likely pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing The R538C variant in the KCNT1 gene has not been reported previously as a pathogenic variant, noras a benign variant, to our knowledge. The R538C variant was not observed in approximately 6300individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The R538C variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species and in silico analysis predicts this variant is probablydamaging to the protein structure/function. The R538C variant is a strong candidate for a pathogenicvariant.
Invitae RCV000804807 SCV000944737 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 538 of the KCNT1 protein (p.Arg538Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNT1-related disease. ClinVar contains an entry for this variant (Variation ID: 390178). 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"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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