Submissions for variant NM_172107.4(KCNQ2):c.553G>A (p.Ala185Thr)

dbSNP: rs1600786349

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000997805	SCV001153523	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068618	SCV001233741	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-12-11	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 185 of the KCNQ2 protein (p.Ala185Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNQ2-related conditions (PMID: 34711204). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 809271). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000997805	SCV001804131	pathogenic	not provided	2023-11-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant resulted in reduced current amplitudes compared to wildtype (Ye et al., 2023); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S3; This variant is associated with the following publications: (PMID: 34711204, 35557555, 36376730, 37497102)
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV001786422	SCV002028373	likely pathogenic	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7	2021-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128266	SCV003804738	likely pathogenic	Seizures, benign familial neonatal, 1	2023-01-31	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS2, PM1, PS4_SUP, PM2_SUP, PP3
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000997805	SCV005198560	likely pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing
GenomeConnect - Brain Gene Registry	RCV001786422	SCV002505365	not provided	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 11-26-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.