ClinVar Miner

Submissions for variant NM_005472.4(KCNE3):c.296G>A (p.Arg99His) (rs121908441)

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Total submissions: 5
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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 RCV000171754 SCV000055273 likely benign Brugada syndrome 2013-06-24 criteria provided, single submitter research
GeneDx RCV000170965 SCV000223528 pathogenic not provided 2011-11-11 criteria provided, single submitter clinical testing p.Arg99His (CGT>CAT): c.296 G>A in exon 3 in the KCNE3 gene (NM_005472.4) The R99H has been reported as a disease-causing mutation in association with Brugada syndrome (Delpon E et al., 2008). Delpon E et al., 2008 was identified to co-segregate with Brugada syndrome in one family with four genotype positive individuals (Delpon E et al., 2008). Although R99H results in conservative amino acid substitution, as these residues share similar properties and are least likely to impact secondary structure; the R99 residue is highly conserved across species. Additionally, R99H was not observed in 406 control alleles (Delpon E et al., 2008) and the R99H mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Of interest, Ohno et al. (2009) reported R99H in a 76 year old Japanese woman with LongQT Syndrome and a history of arrhythmia and drug induced torsades de pointes, possibly the first report of a KCNE3 mutation associated with LQTS. The variant is found in BRUGADA panel(s).
Invitae RCV000005880 SCV000648491 uncertain significance Brugada syndrome 6 2017-03-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 99 of the KCNE3 protein (p.Arg99His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121908441, ExAC 0.03%). This variant was reported to segregate with disease in a family with Brugada syndrome (PMID: 19122847) and was observed in an individual with long QT syndrome (PMID: 19306396).  ClinVar contains an entry for this variant (Variation ID: 5542). Experimental studies using a cell model showed that this variant resulted in an increase in peak current and an accelerated inactivation when co-expressed with KCND3, but did not show an effect in current magnitude when expressed with KCNQ1 (PMID: 19122847, 19306396). The clinical significance of these observations is unclear. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618438 SCV000737959 uncertain significance Cardiovascular phenotype 2017-11-20 criteria provided, single submitter clinical testing Insufficient evidence
OMIM RCV000005880 SCV000026062 pathogenic Brugada syndrome 6 2009-04-01 no assertion criteria provided literature only

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