Submissions for variant NM_005472.5(KCNE3):c.296G>A (p.Arg99His)

gnomAD frequency: 0.00007  dbSNP: rs121908441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171754	SCV000055273	likely benign	Brugada syndrome	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000170965	SCV000223528	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Reported in association with torsades de pointes, cardiomyopathy, congestive heart failure and sudden unexplained death (Ohno et al., 2009; Wang et al., 2017; Lin et al., 2017); Functional studies showed increased current intensity when co-transfected with KCND3, though showed no alteration in current magnitude or kinetics when co-transfected with KCNQ1 (Delpon et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19122847, 30662450, 30821013, 23861362, 29247119, 28855170, 32600061, 19306396)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005880	SCV000648491	uncertain significance	Brugada syndrome 6	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 99 of the KCNE3 protein (p.Arg99His). This variant is present in population databases (rs121908441, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KCNE3-related conditions (PMID: 19122847, 19306396, 28855170, 29247119). ClinVar contains an entry for this variant (Variation ID: 5542). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCNE3 function (PMID: 19122847, 19306396). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000618438	SCV000737959	likely benign	Cardiovascular phenotype	2023-05-04	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000170965	SCV002501671	uncertain significance	not provided	2021-07-09	criteria provided, single submitter	clinical testing
Lildballe Lab, Aarhus University Hospital	RCV000171754	SCV005200533	uncertain significance	Brugada syndrome	2024-03-01	criteria provided, single submitter	research	PM2(sup), PP3(sup), BP6(sup)
OMIM	RCV000005880	SCV000026062	pathogenic	Brugada syndrome 6	2009-04-01	no assertion criteria provided	literature only