Submissions for variant NM_172107.4(KCNQ2):c.838T>C (p.Tyr280His)

dbSNP: rs2081102604

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV001261990	SCV002318880	pathogenic	Developmental and epileptic encephalopathy, 7	2022-03-22	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 27779742). Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic (ClinVar ID: VCV000982412). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000589856). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.983>=0.6, 3CNET: 0.998>=0.75). A missense variant is a common mechanism w. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541583	SCV003443385	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-01-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 27779742; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 982412). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function. This variant disrupts the p.Tyr280 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ2-related conditions (PMID: 32712949), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 280 of the KCNQ2 protein (p.Tyr280His).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001261990	SCV001439352	pathogenic	Developmental and epileptic encephalopathy, 7	2020-09-25	no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315367	SCV004015086	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only