ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000697406 SCV000826014 uncertain significance Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 966 of the KCNT1 protein (p.Ala966Thr). 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 as homozygous due to paternal isodisomy in an individual affected with Ohtahara syndrome (PMID: 24463883). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Athena Diagnostics Inc 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 Epilepsy, nocturnal frontal lobe, 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 likely pathogenic not provided 2019-02-25 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 in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30903923, 24463883, 28488083, 25482562)

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