7-150947708-G-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting
The NM_000238.4(KCNH2):āc.2863C>Gā(p.Leu955Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,585,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2863C>G | p.Leu955Val | missense_variant | Exon 12 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2863C>G | p.Leu955Val | missense_variant | Exon 12 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1843C>G | p.Leu615Val | missense_variant | Exon 8 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3696C>G | non_coding_transcript_exon_variant | Exon 10 of 13 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000257 AC: 5AN: 194206Hom.: 0 AF XY: 0.0000281 AC XY: 3AN XY: 106716
GnomAD4 exome AF: 0.0000586 AC: 84AN: 1433222Hom.: 0 Cov.: 36 AF XY: 0.0000535 AC XY: 38AN XY: 710940
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74462
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:3
BS4, PP2, PM2, PS3_supporting, PS4_moderate -
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) -
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KCNH2: PS4:Moderate, PM2:Supporting, PS3:Supporting -
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Long QT syndrome Pathogenic:1Uncertain:2Other:1
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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. -
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. -
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. -
not specified Uncertain:1
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. -
Cardiovascular phenotype Uncertain:1
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. -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
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Cardiac arrhythmia Uncertain:1
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. 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. -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at