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

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	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 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	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.