Submissions for variant NM_000238.4(KCNH2):c.2863C>G (p.Leu955Val)

gnomAD frequency: 0.00004  dbSNP: rs199473012

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413036	SCV000491005	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies conducted using CHO and HEK cells demonstrated that the L955V variant led to a defect of protein trafficking, resulting in greatly reduced ion current in the plasma membrane (Biliczki et al., 2008); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 18675227, 22581653, 11524404, 33258288, 10973849)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000509284	SCV000828295	uncertain significance	Long QT syndrome	2022-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 955 of the KCNH2 protein (p.Leu955Val). This variant is present in population databases (rs199473012, gnomAD 0.005%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 18675227). ClinVar contains an entry for this variant (Variation ID: 67445). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (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
Color Diagnostics, LLC DBA Color Health	RCV001841729	SCV001351142	uncertain significance	Cardiac arrhythmia	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 955 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant impairs cellular trafficking of the protein and results in reduced potassium channel currents (PMID: 18675227). This variant has been reported in two individuals affected with long QT syndrome (PMID: 18675227, Pacheco et al., 2013) and in an individual affected with sudden unexplained death with a history of syncope (Buscemi et al., 2015). This variant has been identified in 5/194206 chromosomes 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000413036	SCV002502734	likely pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162447	SCV003900776	uncertain significance	Cardiovascular phenotype	2019-12-06	criteria provided, single submitter	clinical testing	The c.2863C>G (p.L955V) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to G substitution at nucleotide position 2863, causing the leucine (L) at amino acid position 955 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000413036	SCV004702766	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	KCNH2: PS4:Moderate, PM2:Supporting, PS3:Supporting
All of Us Research Program, National Institutes of Health	RCV000509284	SCV004835918	uncertain significance	Long QT syndrome	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 955 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant impairs cellular trafficking of the protein and results in reduced potassium channel currents (PMID: 18675227). This variant has been reported in two individuals affected with long QT syndrome (PMID: 18675227, Pacheco et al., 2013) and in an individual affected with sudden unexplained death with a history of syncope (Buscemi et al., 2015). This variant has been identified in 5/194206 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700361	SCV005203013	uncertain significance	not specified	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.2863C>G (p.Leu955Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 194206 control chromosomes, predominantly at a frequency of 6e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.2863C>G has been reported in the literature in individuals affected with Recurrent Syncope, Neurodevelopmental disorders and sudden unexpected death with Peripartum cardiomyopathy by postmortem (Biliczki_2008, Quaio_2020, Grondin_2022, Siskind_2022). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 25% of normal Potassium current, less than 10% of WT proteins from a heterologous expression in human embryonic kidney cells (Biliczki_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18675227, 35352813, 33258288, 36203036). ClinVar contains an entry for this variant (Variation ID: 67445). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000413036	SCV005409402	uncertain significance	not provided	2024-02-22	criteria provided, single submitter	clinical testing	BS4, PP2, PM2, PS3_supporting, PS4_moderate
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.