Submissions for variant NM_172107.4(KCNQ2):c.835G>T (p.Gly279Cys)

dbSNP: rs1057516096

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002436227	SCV002681513	uncertain significance	Inborn genetic diseases	2018-04-20	criteria provided, single submitter	clinical testing	The p.G279C variant (also known as c.835G>T), located in coding exon 6 of the KCNQ2 gene, results from a G to T substitution at nucleotide position 835. The glycine at codon 279 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in one individual in a cohort of individuals with recurrent seizures prior to one month of age, a normal metabolic profile, and a normal brain MRI (Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387836	SCV004099957	likely pathogenic	KCNQ2-related disorder	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: KCNQ2 c.835G>T (p.Gly279Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250870 control chromosomes (gnomAD). c.835G>T has been reported in the literature in at least one individuals affected with KCNQ2-Related Disorders (e.g. Milh_2015). This report does not provide unequivocal conclusions about association of the variant with KCNQ2-Related Disorders. Automated patch clamp assays showed the variant had 4.8% peak current density relative to WT in transfected CHO cells stably expressing KCNQ3 (Vanoye_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25959266, 35104249). One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews	RCV000678142	SCV000484583	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	EE (epileptic encephalopathy)
Channelopathy-Associated Epilepsy Research Center	RCV003315342	SCV004015084	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only