ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2131A>G (p.Ile711Val) (rs199473532)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181838 SCV000234141 pathogenic not provided 2013-11-26 criteria provided, single submitter clinical testing p.Ile711Val (ATC>GTC): c.2131 A>G in exon 8 of the KCNH2 gene (NM_000238.2)The Ile711Val mutation in the KCNH2 gene has been reported in one individual with LQTS and it was absent from 2,600 control alleles (Kapplinger J et al., 2009). Ile711Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. Mutations in nearby residues (Ser706Cys, Ser706Phe, Ala715Val) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, the Ile711Val mutation was not observed with any significant frequency inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.In summary, Ile711Val in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Color RCV000777696 SCV000913629 uncertain significance Arrhythmia 2018-08-28 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that this variant may affect channel gating (PMID: 25417810, 27807201). However, clinical significance of this finding is not clear. This variant has been reported in an individuals affected with long QT syndrome (PMID: 26746457). This variant has also been identified in 9/246208 chromosomes (0.0812%, 8/9850 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058087 SCV000089607 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148537 SCV000190250 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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