Submissions for variant NM_000238.4(KCNH2):c.2266A>G (p.Met756Val)

gnomAD frequency: 0.00001  dbSNP: rs199473534

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001031014	SCV001160808	likely pathogenic	Long QT syndrome 2	2019-12-11	criteria provided, single submitter	research	ACMG evidence PS3, PM2, PP2,PP3,PP5
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001031014	SCV002320705	pathogenic	Long QT syndrome 2	2021-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514287	SCV003019186	uncertain significance	Long QT syndrome	2022-08-21	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67381). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19843919, 23631430). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 756 of the KCNH2 protein (p.Met756Val).
All of Us Research Program, National Institutes of Health	RCV002514287	SCV004834279	uncertain significance	Long QT syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 756 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved cyclic nucleotide binding region (a.a. 742-842). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). In-vitro electrophysiological characterization in transfected CHO cells indicated accelerated inactivation kinetics (PMID: 19843919) and expression levels in transfected HEK293 cells showed over 10% of WT (PMID: 26958806). This variant has been reported in individuals affected with long QT syndrome (PMID: 20850565, 32893267), suspected long QT syndrome (PMID: 23631430), drug-induced long QT syndrome (PMID: 19843919), and an individual affected with epilepsy (PMID: 32238909). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058102	SCV000089622	not provided	Acquired long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with acquired long QT syndrome in the following publications (PMID:19843919). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.