Submissions for variant NM_172107.4(KCNQ2):c.1342C>T (p.Arg448Ter)

dbSNP: rs118192226

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187902	SCV000241504	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11690625, 25525159, 16686649, 18698150, 14534157, 23360469, 28488083, 32712949, 32770121, 20119593, 30202406)
Invitae	RCV000463586	SCV000543196	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg448*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 3360469, 20119593, 25982755). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21762). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000187902	SCV000701213	pathogenic	not provided	2016-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316200	SCV000851205	pathogenic	Inborn genetic diseases	2018-11-23	criteria provided, single submitter	clinical testing	The p.R448* pathogenic mutation (also known as c.1342C>T), located in coding exon 13 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 1342. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple families with neonatal and infantile seizures (Singh NA et al. Brain, 2003 Dec;126:2726-37; Yum MS et al. J. Korean Med. Sci., 2010 Feb;25:324-6; Zara F et al. Epilepsia, 2013 Mar;54:425-36; Grinton BE et al. Epilepsia, 2015 Jul;56:1071-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000720328	SCV001283304	pathogenic	Seizure	2020-05-25	criteria provided, single submitter	clinical testing	Truncating variant absent from gnomAD and recurrent in the litterature.
Lifecell International Pvt. Ltd	RCV003228898	SCV003926488	pathogenic	Developmental and epileptic encephalopathy, 7		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.1258C>T in Exon 11 of the KCNQ2 gene that results in the amino acid substitution p.Arg420* was identified. The observed variant has a maximum allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 21762). The variant has been previously reported by Grinton BE et al, 2015. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
GeneReviews	RCV000020970	SCV000041613	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNIS (benign familial neonatal-infantile seizures)