chr7-150947833-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_000238.4(KCNH2):c.2738C>T(p.Ala913Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,524,188 control chromosomes in the GnomAD database, including 1 homozygotes. 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
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2738C>T | p.Ala913Val | 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.2738C>T | p.Ala913Val | missense_variant | Exon 12 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1718C>T | p.Ala573Val | missense_variant | Exon 8 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3571C>T | non_coding_transcript_exon_variant | Exon 10 of 13 |
Frequencies
GnomAD3 genomes AF: 0.000513 AC: 78AN: 152104Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000400 AC: 48AN: 120030Hom.: 1 AF XY: 0.000411 AC XY: 27AN XY: 65760
GnomAD4 exome AF: 0.000523 AC: 717AN: 1372084Hom.: 1 Cov.: 36 AF XY: 0.000534 AC XY: 361AN XY: 676160
GnomAD4 genome AF: 0.000513 AC: 78AN: 152104Hom.: 0 Cov.: 33 AF XY: 0.000592 AC XY: 44AN XY: 74290
ClinVar
Submissions by phenotype
Long QT syndrome 2 Pathogenic:2Uncertain:2
The KCNH2 c.2738C>T (p.Ala913Val) is a missense variant that has been reported in seven studies in which it is found in a heterozygous state in a total of eleven individuals with either confirmed or suspected long QT syndrome (Tester et al. 2005; Vatta et al. 2006; Kapplinger et al. 2009; Lieve et al. 2013; Trolle et al. 2013; Christiansen et al. 2014; Webster et al. 2019). The p.Ala913Val variant was also detected in a compound heterozygous state in one individual with long QT syndrome who also carried a missense variant in the SCN5A gene. This individual's unaffected father and unaffected sibling also carried the p.Ala913Val variant in a heterozygous state (Hoshi et al. 2015). An individual with atrial fibrillation and mitral valve regurgitation was also reported to be heterozygous for the variant (Gregers et al. 2017). The p.Ala913Val variant was absent from 2,964 control chromosomes (Kapplinger et al. 2009; Christiansen et al. 2014) but is reported at a frequency of 0.002390 in the European (Finnish) population of the Genome Aggregation Database, which includes one homozygote. When the KCNH2 protein bearing the p.Ala913Val variant was expressed in HEK293 cells, electrophysiological measurements showed that there was a 37% reduction in the tail current when compared to wildtype protein. The authors stated that this variant alone was not sufficient to cause long QT syndrome (Hoshi et al. 2015). Gregers et al. (2017) performed similar studies indicating that the variant resulted in a mild gain of function rather than a loss of function. Based on the collective evidence and the application of ACMG criteria, the p.Ala913Val variant is classified as a variant of uncertain significance for long QT syndrome. -
- -
- -
- -
not provided Uncertain:2Benign:2
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar with conflicting classifications (ClinVar Variant ID# 14443; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 24606995, 22245016, 17060380, 26746457, 30704477, 31395126, 25417810, 26213684, 23936059, 26383259, 15840476, 23631430, 14661677, 16540748, 28416588, 32048431, 31737537) -
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)." -
The KCNH2 c.2738C>T; p.Ala913Val variant (rs77331749) is reported in the literature in several individuals affected with long QT syndrome (Hoshi 2015, Kapplinger 2009, Tester 2005, Vatta 2006). This variant is found in the Finnish European population with an overall allele frequency of 0.24% (22/9204 alleles, including one homozygote) in the Genome Aggregation Database. The alanine at codon 913 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.502). Functional studies indicate a modestly reduced current of the variant protein compared to wildtype, although it is uncertain if this difference is clinically significant (Hoshi 2015). Although the population frequency of this variant is inconsistent with disease, since a low penetrance effect cannot be ruled out, the clinical significance of the p.Ala913Val variant is uncertain at this time. References: Hoshi M et al. Polygenic Case of Long QT Syndrome Confirmed through Functional Characterization Informs the Interpretation of Genetic Screening Results. HeartRhythm Case Rep. 2015 Jul 1;1(4):201-205. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. Vatta M et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006 Nov 14;114(20):2104-12. -
- -
Long QT syndrome Uncertain:1Benign:1
- -
- -
Long QT syndrome 2/9, digenic Pathogenic:1
- -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Cardiac arrhythmia Benign:1
- -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at