ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.862G>A (p.Gly288Ser) (rs587777264)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255411 SCV000321803 pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing The G288S variant in the KCNT1 gene was identified in two unrelated individuals with malignant migrating partial seizures in infancy and was reported to have occured de novo, although maternity and paternity were not confirmed (Ishii et al., 2013). This variant has also been identified at GeneDx as a confirmed de novo variant in a patient with infantile-onset epileptic encephalopathy. The G288S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G288S as a pathogenic variant.
Invitae RCV000627792 SCV000553815 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 288 of the KCNT1 protein (p.Gly288Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with epilepsy, most of whom displayed malignant migrating partial seizures in infancy (PMID: 24029078, 26122718, 26140313, 26597493). In several of these individuals, this variants was reported to be de novo (PMID: 24029078, 26122718, 26140313). 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: Probably Damaging; Align-GVGD: Class C0). However, this variant occurs in the pore region of the KCNT1 channel and computational molecular analysis suggests that it affects the structure of the channel (PMID: 24029078). These predictions have not been confirmed by published functional studies. In summary, this is a rare missense variant that is absent from the general population and reported in many individuals with disease. Therefore, it has been classified as Pathogenic.
Baylor Genetics RCV000114361 SCV000807324 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
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000114361 SCV001433979 pathogenic Early infantile epileptic encephalopathy 14 criteria provided, single submitter clinical testing 20A3406
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265540 SCV001443687 pathogenic Epilepsy, nocturnal frontal lobe, 5 2019-12-04 criteria provided, single submitter clinical testing This variant is a recurrent gain of function alteration at a CG dinucleotide sequence in the pore region of the KCNT1 channel. The c.862G>A variant has been reported either as a de novo change or with unknown inheritance in several children with typical migrating malignant partial seizures in infancy (MMPSI) (PMID: 24029078, 26122718, 26140313, 30185235, 26993267, 25482562). Severe delayed myelination was reported in three of these patients (PMID: 26597493, 25482562). Two of these children had seizures that were initially resistant to different drugs, and responded to vagus nerve stimulation or clorazepate (PMID: 24029078). The c.862G>A, p.Gly288Ser variant was also identified in a child with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (PMID: 25482562). Other KCNT1 missense variants, including a recurrent c.1283G>A alteration identified in three sporadic cases, are located at CG dinucleotides, suggesting that the CpG dinucleotide at these various KCNT1 positions, may be hot spots for point mutations. Functional characterization of the c.862G>A, p.Gly288Ser alteration using heterologous systems showed an increased KCNT1 current (PMID: 26784557, 25482562). The c.862G>A, p.Gly288Ser is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In addition, it affects a highly conserved amino acid and is predicted to have a deleterious effect on protein function by the majority of in silico tools used for the analysis. The c.862G>A, p.Gly288Ser variant is reported in ClinVar (Variation ID: 126421). Based on the available evidence, the c.862G>A, p.Gly288Ser variant is classified as Pathogenic.
OMIM RCV000114361 SCV000147973 pathogenic Early infantile epileptic encephalopathy 14 2013-12-01 no assertion criteria provided literature only

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