ClinVar Miner

Submissions for variant NM_000891.2(KCNJ2):c.277G>A (p.Val93Ile) (rs147750704)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148540 SCV000190253 uncertain significance Atrial fibrillation 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000148540 SCV000089827 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:15922306;PMID:19041665). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000170978 SCV000223541 likely pathogenic not provided 2016-05-17 criteria provided, single submitter clinical testing The V93I variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. Additionally, V93I is located in the M1 transmembrane helix. However, the V93I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, this substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, and Isoleucine is tolerated at this position in multiple species. Therefore, this variant is likely pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000023029 SCV000914783 uncertain significance Atrial fibrillation, familial, 9 2017-10-18 criteria provided, single submitter clinical testing The KCNJ2 c.277G>A (p.Val93Ile) variant has been reported one study in association with familial atrial fibrillation (AF) in which it is found in a heterozygous state in all five affected members of the same Chinese Han family; the proband, two siblings, father and niece (Xia et al. 2005). The proband had paroxysmal AF two to three times a month. His father and older sister were in permanent AF prior to death, his younger sister suffered from paroxysmal AF once or twice a week and his niece showed paroxysmal AF on a 24 hour ECG. All affected individuals were greater than 50 years of age at diagnosis. The variant was also found in a heterozygous state in two nephews, neither of whom showed paroxysmal AF on a 24 hour ECG, but who were 42 and 33 years of age at the time of study. The variant was not found in any other unaffected family members. The p.Val93Ile variant was also absent from 420 unrelated healthy Chinese individuals but is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Consortium. The p.Val931Ile variant is located in the outer helix of the M1 transmembrane domain of the protein which is a highly conserved region. Electrophysiological evaluation using whole-cell patch-clamping in COS-7 and HEK293 cells showed higher amplitude potentials compared to wildtype, demonstrating a gain of function effect of the variant on inward and outward KCNJ2 currents (Xia et al. 2005). Based on the evidence, the p.Val93Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial atrial fibrillation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000544361 SCV000645184 uncertain significance Andersen Tawil syndrome; Short QT syndrome 3 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 93 of the KCNJ2 protein (p.Val93Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs147750704, ExAC 0.03%). This variant has been reported in one family affected with atrial fibrillation (PMID: 15922306), and in one individual referred for long QT syndrome genetic testing (PMID: 23631430). It has also been observed in individuals who did not have atrial fibrillation (PMID: 15922306, 25410959). ClinVar contains an entry for this variant (Variation ID: 30121). While experimental studies have shown that this missense change leads to an increase in potassium current amplitudes (PMID: 15922306, 19041665), the relationship between this observation and atrial fibrillation is unclear (PMID: 19111761). 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.
OMIM RCV000023029 SCV000044320 pathogenic Atrial fibrillation, familial, 9 2005-07-15 no assertion criteria provided literature only

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