7-150974861-C-G

Position:

• chr7-150974861-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G53C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150974860-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67217.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
KCNH2	NM_000238.4	c.157G>C	p.Gly53Arg	missense_variant	2/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.157G>C	p.Gly53Arg	missense_variant	2/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.380G>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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:1 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.93
Sift	Benign	0.043	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of catalytic residue at S55 (P = 0.0804);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199472842; hg19: chr7-150671949;