7-150974861-C-G
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.157G>C(p.Gly53Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
KCNH2
NM_000238.4 missense
NM_000238.4 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 6.03
Genes affected
KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a domain PAS (size 29) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 7-150974861-C-G is Pathogenic according to our data. Variant chr7-150974861-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150974861-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.157G>C | p.Gly53Arg | missense_variant | Exon 2 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2022 | Identified in patients with LQTS in the published literature and in a patient with LQTS referred for genetic testing at GeneDx (Splawski et al., 2000; Tester et al., 2005); Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via channel deactivation or trafficking defect (Chen et al., 1999; Harley et al., 2012; Anderson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 67215); This variant is associated with the following publications: (PMID: 10187793, 15840476, 21536673, 23303164, 22396785, 32475984, 10973849, 25417810) - |
Congenital long QT syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10187793;PMID:10973849;PMID:15840476;PMID:21536673;PMID:22396785). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 14, 2018 | The p.Gly53Arg variant in KCNH2 has been reported in at least 4 individuals with Long QT syndrome (LQTS; Splawski 2000, Haraguchi 2005, Tester 2005, Goldenberg 2011), and was absent from large population studies. In vitro functional studies provide some evidence that the p.Gly53Arg variant may impact protein trafficking, although effects of the variant on gating potential are conflicting (Chen 1999, Gianulis 2011, Harley 2012, Anderson 2014). An animal model in zebrafish has shown that this variant cannot rescue wildtype levels of repolorization (Jou 2013). Note, these types of assays may not accurately represent biological function. This variant has been reported in ClinVar (Variation ID: 67215). Computational prediction tools and conservation analysis suggest that the p.Gly53Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly53Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderate, PM2, PS4_Supporting, PP3. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2020 | The p.G53R variant (also known as c.157G>C), located in coding exon 2 of the KCNH2 gene, results from a G to C substitution at nucleotide position 157. The glycine at codon 53 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a patient with Long QT Syndrome Type 2 (LQT2) (Haraguchi Y et al. Circ. J., 2005 Jan;69:78-82). Functional studies indicate that this alteration will impact protein function (Chen J et al. J. Biol. Chem., 1999 Apr;274:10113-8; Gianulis EC et al. J. Biol. Chem., 2011 Jun;286:22160-9; Anderson CL et al. Nat Commun, 2014 Nov;5:5535). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is located within the PAS domain of KCNH2 and is expected to disrupt trafficking and lead to deactivation of the potassium channel (Chen J et al. J. Biol. Chem., 1999 Apr;274:10113-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 09, 2019 | This missense variant replaces glycine with arginine at codon 53 in the cytoplasmic N-terminal PAS domain 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that the mutant protein is defective for protein maturation and trafficking to the cell surface (PMID: 22396785, 25417810, 26958806), but shows normal function if successfully transported to the cell surface (PMID: 26958806). This variant has been reported in multiple long QT syndrome patients (PMID: 10973849, 15635208 15840476) and may also present as concealed long QT syndrome (PMID: 21185501). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position (p.Gly53Asp) has also been observed in a long QT syndrome patient (PMID: 19716085). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Uncertain
T
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at S55 (P = 0.0804);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at