Submissions for variant NM_004519.4(KCNQ3):c.988C>T (p.Arg330Cys)

dbSNP: rs118192251

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000462450	SCV000543210	pathogenic	Benign neonatal seizures	2023-05-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ3 protein function. ClinVar contains an entry for this variant (Variation ID: 21417). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 18249525, 23146207). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the KCNQ3 protein (p.Arg330Cys).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000020602	SCV000743523	pathogenic	Seizures, benign familial neonatal, 2	2014-10-08	criteria provided, single submitter	clinical testing
3billion	RCV000020602	SCV002012197	likely pathogenic	Seizures, benign familial neonatal, 2	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23146207, PS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3Cnet: 0.981, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV003233074	SCV003931034	pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate abnormal channel function (Miceli et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23146207, 16883520, 28717674, 35627257, 34474328, 18249525, 25524373, 34136434)
GeneReviews	RCV000020602	SCV000041091	not provided	Seizures, benign familial neonatal, 2		no assertion provided	literature only	Same variant detected in 2 unrelated families
OMIM	RCV000020602	SCV000121585	pathogenic	Seizures, benign familial neonatal, 2	2013-05-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000020602	SCV000734592	pathogenic	Seizures, benign familial neonatal, 2		no assertion criteria provided	clinical testing