rs199473419

chr7-150974809-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000238.4(KCNH2):c.209A>G(p.His70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H70N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.56

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 14 ACMG points.

• PM1: In a hotspot region, there are 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 7-150974809-T-C is Pathogenic according to our data. Variant chr7-150974809-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150974809-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.209A>G	p.His70Arg	missense_variant	2/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.209A>G	p.His70Arg	missense_variant	2/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.432A>G		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 26, 2021	PS3, PS4_Moderate, PM1, PM2_Supportingm PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on channel trafficking and/or channel function (Chen et al., 1999; Jou et al., 2013; Anderson et al., 2014; Perry et al., 2016); however, some conflicting studies suggest this variant may have little to no effect on these properties (Gianulis et al., 2011; Harley et al., 2012; Perry et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22396785, 22949429, 23303164, 10973849, 15840476, 11854117, 19841300, 19716085, 10187793, 21536673, 26105569, 15051636, 25294783, 22885918, 26958806, 30012873, 22581653, 33729832, 32475984, 25417810) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 70 of the KCNH2 protein (p.His70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 11854117, 22949429, 25294783; Invitae). ClinVar contains an entry for this variant (Variation ID: 67363). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 10187793, 21536673, 22396785, 23303164). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2020

The p.H70R variant (also known as c.209A>G), located in coding exon 2 of the KCNH2 gene, results from an A to G substitution at nucleotide position 209. The histidine at codon 70 is replaced by arginine, an amino acid with highly similar properties, and is located in the PAS domain. This alteration has been detected in individuals reported to have long QT syndrome (LQTS) (Kapa S et al. Circulation. 2009;120:1752-60; Westenskow P et al. Circulation. 2004;109:1834-41; Vijayakumar R et al. Circulation. 2014;130:1936-43) and has also been detected in LQTS cohorts for which clinical details were limited or not provided, and reports may overlap (Splawski I et al. Circulation. 2000;102:1178-85; Moss AJ et al. Circulation, 2002;105:794-9; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Medlock MM et al. Heart Rhythm. 2012;9:1977-82). In vitro analyses of this alteration have suggested both accelerated rate of channel deactivation in the Xenopus oocyte model, and a rate similar to wild type using HEK293 cells (Chen J et al. J. Biol. Chem. 1999;274:10113-8; Anderson CL et al. Nat Commun. 2014;5:5535; Gianulis EC et al. J Biol Chem. 2011;286:22160-9). Another study using zebrafish reported this alteration to result in reduced cardiac repolarization and reduced ability to rescue knockouts compared to wild type (Jou CJ et al. Circ Res. 2013;112:826-30). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. 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. -

Congenital long QT syndrome 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:11854117;PMID:15051636;PMID:15840476;PMID:19716085;PMID:19841300;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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
CardioboostArm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	27
Dann	Benign	0.90
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Benign	0.072
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.67	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	D;.
REVEL	Pathogenic	0.82
Sift	Benign	0.17	T;.
Sift4G	Benign	0.21	T;T
Polyphen		0.99	D;.
Vest4		0.72
MVP		0.99
MPC		2.1
ClinPred		0.49	T
GERP RS		4.4
Varity_R		0.67
gMVP		0.97

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: rs199473419; hg19: chr7-150671897;