ClinVar Miner

Submissions for variant NM_000890.5(KCNJ5):c.1190A>G (p.Glu397Gly)

gnomAD frequency: 0.00002  dbSNP: rs780934792
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000531349 SCV000627597 likely benign Long QT syndrome 2023-09-01 criteria provided, single submitter clinical testing
GeneDx RCV000786147 SCV002559275 uncertain significance not provided 2022-07-29 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002341266 SCV002640736 uncertain significance Cardiovascular phenotype 2021-11-15 criteria provided, single submitter clinical testing The p.E397G variant (also known as c.1190A>G), located in coding exon 2 of the KCNJ5 gene, results from an A to G substitution at nucleotide position 1190. The glutamic acid at codon 397 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786147 SCV000924820 uncertain significance not provided 2017-04-17 no assertion criteria provided provider interpretation Found in a 7-year-old girl with a borderline QTc interval, and prolongation to 490 msec on exercise test, but no solid clinical diagnosis of LQTS. She had genetic testing for long QT syndrome with the Invitae laboratory. The following genes were evaluated for sequence changes and exonic deletions/duplications: AKAP9, ANK2, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1, TRDN. One variant was detected: p.Glu397Gly (E397G; c.1190A>G) in exon 3 of the KCNJ5 gene (NM_000890.3) Chromosome position 11:128786556 A / G Based on the information reviewed below, we classify this as Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. We believe it is more likely to be a benign ethnicity-specific variant among Latinos. This variant has not been reported in the literature in association with disease. This is a non-conservative amino acid change, resulting in the replacement of a negatively-charged Glutamic Acid with a nonpolar Glycine. Glutamic Acid at this location is poorly conserved across vertebrate species (alternate amino acids include Lysine, Glutamine, Threonine, Serine, Aspartic Acid…). In fact, Glycine is the default amino acid in at least three species for which we have data. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant was reported in 13 individuals in the gnomAD database, and all of them have Latino ancestry like our patient. Latino allele frequency: 0.04% (~1 in 1280 people). It was not reported in any other ancestry group. This database includes variant calls on ~121,200 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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