ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1843C>G (p.Leu615Val) (rs199473012)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413036 SCV000491005 likely pathogenic not provided 2016-03-10 criteria provided, single submitter clinical testing The L955V likely pathogenic variant in the KCNH2 gene has been reported in a 5 year-old female with history ofrecurrent syncope and slightly prolonged QTc interval (Biliczki et al., 2008). Subsequently, L955V was identified ina female proband with history of a syncopal episode at age 10 and sudden unexplained death at age 13 (Buscemi etal., 2015). In the same study, clinical evaluation of relatives confirmed that the proband's maternal aunt had aprolonged QTc interval; however, it is unclear whether the affected aunt harbored the L955V variant (Buscemi et al.,2015). Moreover, the L955V variant was not observed in approximately 6,200 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project (average read depth 6X). Although the L955V variant isa conservative amino acid substitution, this substitution occurs at a position that is conserved in mammalian species.Functional studies conducted using CHO and HEK cells demonstrated that the L955V variant led to a severe defect ofprotein formation and transportation, resulting in greatly reduced ion current in the plasma membrane (Biliczki et al.,2008). Therefore, this variant is likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000509284 SCV000748000 likely pathogenic Long QT syndrome 2017-03-21 criteria provided, single submitter clinical testing
Invitae RCV000509284 SCV000828295 uncertain significance Long QT syndrome 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 955 of the KCNH2 protein (p.Leu955Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs199473012, ExAC 0.01%). This variant has been observed in an individual affected with long QT syndrome (PMID: 18675227). ClinVar contains an entry for this variant (Variation ID: 67445). Experimental studies have shown that this missense change causes a trafficking deficiency, potential aggregate formation and decreased function of the ion channel (PMID: 18675227). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000413036 SCV000884047 likely pathogenic not provided 2017-11-06 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058172 SCV000089692 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:18675227). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GenomeConnect, ClinGen RCV000509284 SCV000606894 not provided Long QT syndrome no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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