ClinVar Miner

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

gnomAD frequency: 0.00338  dbSNP: rs17215437
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Total submissions: 18
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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
Invitae 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

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