Submissions for variant NM_172107.4(KCNQ2):c.431G>A (p.Arg144Gln)

dbSNP: rs796052618

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187853	SCV000241453	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32860008, 28628100, 23934111, 25740509, 29186148, 30440138, 29655203, 30174244)
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000408747	SCV000598136	pathogenic	Developmental and epileptic encephalopathy, 7	2016-06-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000187853	SCV001249243	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000408747	SCV001426583	pathogenic	Developmental and epileptic encephalopathy, 7		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000187853	SCV001448113	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV001386878	SCV001587273	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-06-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 25740509). 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. ClinVar contains an entry for this variant (Variation ID: 205864). This variant is also known as chr20:62076674 C>T. This missense change has been observed in individual(s) with clinical features of KCNQ2-related conditions (PMID: 23934111). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 144 of the KCNQ2 protein (p.Arg144Gln).
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV000187853	SCV001760741	likely pathogenic	not provided	2020-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528968	SCV004109351	pathogenic	KCNQ2-related disorder	2023-09-06	criteria provided, single submitter	clinical testing	The KCNQ2 c.431G>A variant is predicted to result in the amino acid substitution p.Arg144Gln. This variant has been documented as de novo in multiple individuals with KCNQ2 related disorders, and functional studies support its pathogenicity (Table S12, Allen et al. 2013. PubMed ID: 23934111; Table S4, Geisheker et al. 2017. PubMed ID: 28628100; Table S2, Zhu et al. 2017. PubMed ID: 29186148; Table S4, Lindy et al. 2018. PubMed ID: 29655203; Yuskaitis et al. 2018. PubMed ID: 30174244). At PreventionGenetics, we have observed this variant to have occurred de novo in an individual with neurodevelopmental features and seizures. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
GeneReviews	RCV000408747	SCV000484553	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	Infantile spasms
Diagnostic Laboratory, Strasbourg University Hospital	RCV001089802	SCV001244216	likely pathogenic	Intellectual disability	2016-12-01	no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315313	SCV004015056	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only