Submissions for variant NM_172107.4(KCNQ2):c.916G>A (p.Ala306Thr)

dbSNP: rs74315390

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002316186	SCV000851351	pathogenic	Inborn genetic diseases	2019-11-25	criteria provided, single submitter	clinical testing	The p.A306T pathogenic mutation (also known as c.916G>A), located in coding exon 6 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 916. The alanine at codon 306 is replaced by threonine, an amino acid with similar properties. This mutation was originally identified in a large family, which showed significant linkage to the KCNQ2 locus on chromosome 20 (Singh NA et al. Nat. Genet., 1998 Jan;18:25-9). Subsequently, this mutation has been reported in patients with neonatal seizures or infantile spasms (Soldovieri MV et al. Hum. Mutat., 2014 Mar;35:356-67; Dimassi S et al. Clin. Genet., 2016 Feb;89:198-204). An in vitro study showed that A306T, located in transmembrane domain S6, reduces potassium currents (Schroeder BC et al. Nature, 1998 Dec;396:687-90). Furthermore, A306T knock-in mice have reduced thresholds to electrically induced seizure and increased sensitivity to chemical convulsant (Singh NA et al. J. Physiol. (Lond.), 2008 Jul;586:3405-23; Otto JF et al. Epilepsia, 2009 Jul;50:1752-9; Tomonoh Y et al. PLoS ONE, 2014 Feb;9:e88549). Based on the available evidence, p.A306T is classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245227	SCV001418500	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 306 of the KCNQ2 protein (p.Ala306Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 9425895, 14534157, 24375629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7382). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 18483067, 19453707). This variant disrupts the p.Ala306 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25959266, 26704558, 27535030). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001564572	SCV001787757	pathogenic	not provided	2022-04-15	criteria provided, single submitter	clinical testing	Reported in a family with benign familial neonatal seizures (Singh et al., 1998); Published functional studies demonstrate altered excitability of the M-type K+ channel, reduction of seizure threshold, and altered susceptibility to kindling-acquisition in a mouse model (Otto et al., 2009); The majority of missense variants in this gene are considered pathogenic (HGMD); This substitution is predicted to be within the transmembrane segment S6; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26138355, 19453707, 9425895, 28717674, 24586341)
Institute of Human Genetics, University of Leipzig Medical Center	RCV002264637	SCV005368377	pathogenic	Developmental and epileptic encephalopathy, 7	2024-09-30	criteria provided, single submitter	clinical testing	Criteria applied: PS2,PS4,PM5_STR,PM1,PM2,PP3
OMIM	RCV000007807	SCV000028008	pathogenic	Seizures, benign familial neonatal, 1	1998-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000007807	SCV000041664	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy). 11/69 FS (febrile seizures); GS (generalized seizures) between 1 and 16 years.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV002264637	SCV002546233	pathogenic	Developmental and epileptic encephalopathy, 7		no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315291	SCV004015102	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only