ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.3493A>G (p.Thr1165Ala)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001052422 SCV001216632 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2019-03-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1165 of the KCNT1 protein (p.Thr1165Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs549276113, ExAC 0.02%). This variant has not been reported in the literature in individuals with KCNT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
New York Genome Center RCV001281482 SCV001468790 uncertain significance Seizures 2019-07-24 criteria provided, single submitter clinical testing The inherited c.3493A>G (p.Thr1165Ala) variant identified in the KCNT1 gene substitutes a highly conserved Threonine for Alanine at amino acid 1165/1236 (coding exon 29/31). This variant is found with low frequency in gnomAD (1 heterozygote, 0 homozygotes; allele frequency: 4.852e-6) and ExAC (1 heterozygote, 0 homozygotes; allele frequency: 1.659e-5), suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms predict this variant to be Neutral (Provean; score: -0.59) and Tolerated (SIFT; score: 0.646) to the function of the canonical transcript. This variant is absent from ClinVar and currently has not be reported in any affected individuals in the literature. The p.Thr1165 residue is not within a specific functional domain, but is found in the long intracellular C-terminal region where other KCNT1 pathogenic missense variants have been reported [; PMID: 26122718]. Given the lack of compelling information supporting the pathogenicity of the inherited c.3493A>G (p.Thr1165Ala) variant in KCNT1, it is reported here as a Variant of Uncertain Significance.

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