ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2738C>T (p.Ala913Val) (rs77331749)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000015526 SCV000206998 likely pathogenic Long QT syndrome 2 2015-04-30 criteria provided, single submitter clinical testing
GeneDx RCV000181887 SCV000234190 uncertain significance not specified 2017-01-04 criteria provided, single submitter clinical testing p.Ala913Val (GCG>GTG): c.2738 C>T in exon 12 of the KCNH2 gene (NM_000238.2). The A913V variant in the KCNH2 gene has been published previously in multiple individuals with LQTS, and was not detected in over 2,600 control alleles (Tester D et al., 2005; Kapplinger J et al., 2009). The A913V variant was also identified in one individual with LQTS who in addition harbored a published CAV3 variant (Vatta M et al., 2006). Although this evidence might suggest that A913V is pathogenic, the A913 residue is not highly conserved across species as, for example, a Valine residue is present in the mouse homolog. In silico analysis predicts A913V likely has a benign effect on the protein structure/function. Moreover, several benign polymorphisms in neighboring residues within the C-terminus (P910L, A915V, P917L) have been identified in healthy control individuals, indicating this region of the protein may be tolerant of change (Modell S et al., 2006; Ackerman M et al., 2003). A913V also was observed in 1 out of 400 Caucasian control alleles tested at GeneDx. Data from the NHLBI Exome Sequencing Project and 1000 Genomes database were not available to assess whether A913V may be a common benign variant in the general population.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000204621 SCV000259492 likely benign Long QT syndrome 2020-11-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589886 SCV000696026 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.2738C>T (p.Ala913Val) variant is located in the C-terminus causing a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this variant. The variant of interest was not found in controls (ExAC, ESP, 1000 Gs, or publication controls). Multiple publications cite the variant in affected individuals including the variant to co-occur with a known CAV3 mutation, T78M, along with another KCNH2 variant, S654V (not yet scored), along with evidence for lack of cosegregation within one family (Hoshi_2015). Functional studies have implicated that the variant has a mild affect on wild type function (Hoshi_2015), along with the authors further suggested that the variant alone does not cause disease (Hoshi_2015). In addition, a recent independent study performed by Van Driest_2016, in which expert reviews were performed by three independent clinical laboratories to assess classification of this variant, two out of the three laboratories indicated the variant to not be pathogenic. Furthermore, multiple reputable clinical laboratories have provided conflicting classifications, "uncertain significance," "likely pathogenic," or "pathogenic." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Ambry Genetics RCV000620709 SCV000735138 uncertain significance Cardiovascular phenotype 2020-06-23 criteria provided, single submitter clinical testing The p.A913V variant (also known as c.2738C>T), located in coding exon 12 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2738. The alanine at codon 913 is replaced by valine, an amino acid with similar properties, and is located in the C-terminal region of the protein. This variant has been reported in cohorts with a variety of phenotypes, including long QT syndrome, dilated cardiomyopathy, atrial fibrillation, and sudden death; however, clinical details were frequently limited and other variants were detected in some cases (Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Vatta M et al. Circulation. 2006;114(20):2104-12; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17(7):553-61; Trolle C et al. PLoS One. 2013;8(7):e69614; Christiansen M et al. BMC Med Genet. 2014;15:31; Hertz CL et al. Int. J. Legal Med. 2016;130(1):91-102; Hertz CL et al. Int. J. Legal Med. 2016;130(1):91-102; Gregers E et al. Heart Rhythm. 2017;14(10)). In an in vitro functional study, a 37% decrease in tail current in the homozygous state was observed; a follow-up in silico analysis predicted a 30-ms prolongation of the action potential duration at 90% repolarization (Hoshi M et al. HeartRhythm Case Rep. 2015;1(4):201-205). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000204621 SCV000740341 uncertain significance Long QT syndrome 2017-01-27 criteria provided, single submitter clinical testing
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000015526 SCV000805120 uncertain significance Long QT syndrome 2 2017-11-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771357 SCV000903647 likely benign Arrhythmia 2018-04-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589886 SCV001502620 likely benign not provided 2020-08-01 criteria provided, single submitter clinical testing
OMIM RCV000015526 SCV000035791 pathogenic Long QT syndrome 2 2006-11-14 no assertion criteria provided literature only
OMIM RCV000015527 SCV000035792 pathogenic Long QT syndrome 2/9, digenic 2006-11-14 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058156 SCV000089676 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:15840476;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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