ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.2896G>A (p.Ala966Thr)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000697406 SCV000826014 likely pathogenic Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5 2022-06-03 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNT1 function (PMID: 24463883, 25482562). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 575241). This missense change has been observed in individuals with KCNT1-related conditions (PMID: 24463883, 30903923; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 966 of the KCNT1 protein (p.Ala966Thr).
Athena Diagnostics RCV000712127 SCV000842549 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001004685 SCV001164142 pathogenic Autosomal dominant nocturnal frontal lobe epilepsy 5 2017-08-04 criteria provided, single submitter clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001290124 SCV001469057 pathogenic Malignant migrating partial seizures of infancy criteria provided, single submitter clinical testing 10A4294
GeneDx RCV000712127 SCV001768131 pathogenic not provided 2023-09-14 criteria provided, single submitter clinical testing Reported previously in association with Ohtahara syndrome in an affected individual who was homozygous for the A966T variant due to paternal isodisomy (Martin et al., 2014). Functional studies showed a significant increase in channel activity compared to wild type, which is thought to account for the epileptic activity seen in this individual with Ohtahara syndrome (Martin et al., 2014); Functional studies in rat showed increased currents, similar to other pathogenic KCNT1 variants (Kim et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25482562, 28488083, 24463883, 30903923, 27064559, 36499459, 34911427, 25985138, 34114611)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000697406 SCV003920110 uncertain significance Developmental and epileptic encephalopathy, 14; Autosomal dominant nocturnal frontal lobe epilepsy 5 2021-12-07 criteria provided, single submitter clinical testing KCNT1 NM_020822.2 exon 25 p.Ala966Thr (c.2896G>A): This variant has been reported in the literature in 1 individual with Ohtahara syndrome in the homozygous state, likely due to paternal uniparental disomy (UPD) (Martin 2014 PMID:24463883). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:575241). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. Functional studies in Xenopus laevis oocytes have suggested that this variant may impact the protein and increase channel activity; however, these studies may not accurately represent human in vivo biological function (Kim 2014 PMID: 25482562, Martin 2014 PMID:24463883). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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