Submissions for variant NM_005472.5(KCNE3):c.248G>A (p.Arg83His)

gnomAD frequency: 0.00338  dbSNP: rs17215437

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171813	SCV000050824	benign	Periodic paralysis	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000005879	SCV000223524	benign	not provided	2018-07-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: none, 11207363, 11874988, 24055113, 12414843, 14504341, 15037716, 20051516)
Ambry Genetics	RCV000253742	SCV000318064	likely benign	Cardiovascular phenotype	2018-05-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415218	SCV000492900	uncertain significance	Syncope; Ventricular fibrillation	2014-07-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223897	SCV000539422	uncertain significance	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Several pubs, including possible segs and functional studies, but frequency is too high for disease and wrong phenotype. ExAC: 0.4% (289/66352) European chromosomes
CeGaT Center for Human Genetics Tuebingen	RCV000005879	SCV000574898	benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	KCNE3: BS1, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538199	SCV000648490	benign	Brugada syndrome 6	2024-01-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000538199	SCV000743882	likely benign	Brugada syndrome 6	2014-10-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000538199	SCV000884045	likely benign	Brugada syndrome 6	2023-10-03	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852657	SCV000995363	likely benign	Cardiomyopathy	2019-01-10	criteria provided, single submitter	clinical testing
Mendelics	RCV000988595	SCV001138374	benign	Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000538199	SCV001367235	uncertain significance	Brugada syndrome 6	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000005879	SCV001714385	uncertain significance	not provided	2020-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223897	SCV004803732	likely benign	not specified	2024-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000005879	SCV000026061	uncertain significance	not provided	2007-04-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223897	SCV000280114	uncertain significance	not specified	2012-12-11	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNE3 p.Arg83His Based on the data reviewed below we consider it a variant of uncertain significance, probably benign. The variant has been reported in cases of periodic paralysis (Abbot et al 2001, Dias Da Silva et al 2002, Sterberg et al 2003). However, it was then later found in controls, suggesting it is likely benign and was identified in these cases because it is present in 0.1-1% of all individuals (reviewed in more detail below). Hedley et al (2011) investigated the KCNE genes as putative HCM genes. In their cohort of 93 unrelated HCM patients two individuals had p.Arg83His in KCNE3. However, the authors concluded it was not causative since one of the patients also had a presumed pathogenic TNNT2 variant (specific variant not cited) and because of the prevalence in the general population. In silico analysis with PolyPhen-2 predicts the variant to be benign. The arginine at codon 83 is not conserved across species and in the marmoset is in fact a histidine. The KCNE3 gene has been associated with Brugada syndrome type 6 (Deplon et al 2008) and periodic paralysis (Abbott et al 2001). In total the variant has not been seen with allele frequencies of 0.1-1.1% in individuals in general population samples (rs17215437). Another variant, c.248G>T has been seen with allele frequencies of 0.14-1.52% in 1000 genomes. The variant was recently reported online in 50 of 5379 individuals in the NHLBI Exome Sequencing Project dataset (as of December 11th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.
Clinical Genetics, Academic Medical Center	RCV000223897	SCV001918148	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000005879	SCV001956677	likely benign	not provided		no assertion criteria provided	clinical testing