ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.2800G>A (p.Ala934Thr) (rs397515403)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000032794 SCV000807331 pathogenic Early infantile epileptic encephalopathy 14 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found twice in our laboratory de novo in individuals with infantile onset epileptic encephalopathy
GeneDx RCV000494477 SCV000582546 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The A934T pathogenic variant in the KCNT1 gene has been reported previously in individuals with malignant migrating partial seizures of infancy (Barcia et al., 2012; McTague et al., 2013). Functional studies indicate that the A934T variant causes a marked increase in KCNT1 protein function; the mutant channel activates significantly more quickly than wild-type channels with greater current amplitude (Barcia et al., 2012; Milligan et al., 2014). The A934T variant is not observed in large population cohorts (Lek et al., 2016). The A934T variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. We interpret A934T as a pathogenic variant.
Invitae RCV000791441 SCV000290487 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 934 of the KCNT1 protein (p.Ala934Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with early-onset epileptic encephalopathy, including malignant migrating partial seizures of infancy (PMID: 23086397, 25482562, 26993267, 26122718, 26140313). In three of these individuals, the variant was found to be de novo (PMID: 23086397, 26140313, 26993267), and in another the variant was inherited from an unaffected mother who was mosaic for this variant (PMID: 26122718). ClinVar contains an entry for this variant (Variation ID: 39594). Experimental studies have shown that this missense change renders the KCNT1 ion channel constitutively active, when assayed in cell culture (PMID: 23086397, 24591078). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000032794 SCV000056562 pathogenic Early infantile epileptic encephalopathy 14 2012-11-01 no assertion criteria provided literature only

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