rs199472922

Positions:

• chr7-150951708-T-C
• chr7-150951708-T-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.1685A>G​(p.His562Arg) variant causes a missense change involving the alteration of a 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. H562P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.83

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr7-150951708-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-150951708-T-C is Pathogenic according to our data. Variant chr7-150951708-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1685A>G	p.His562Arg	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1685A>G	p.His562Arg	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jul 11, 2022

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 562 of the KCNH2 protein (p.His562Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 19716085, 25819988; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67232). 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: 25417810). This variant disrupts the p.His562 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 15242738), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2018

The p.H562R variant (also known as c.1685A>G), located in coding exon 7 of the KCNH2 gene, results from an A to G substitution at nucleotide position 1685. The histidine at codon 562 is replaced by arginine, an amino acid with highly similar properties. This alteration has been identified in long QT syndrome cohorts; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Aziz PF et al. Circ Arrhythm Electrophysiol. 2011;4:867-73; Itoh H et al. Eur J Hum Genet. 2016;24:1160-6; Izumi G et al. Pediatr Cardiol. 2016;37:962-70). This variant was reported to segregate with disease in two families (Allegue C et al. Int. J. Legal Med., 2011;125:565-72; Muñoz-Esparza C et al. Rev Esp Cardiol (Engl Ed). 2015;68:861-8). Functional studies suggest that this alteration has a dominant negative effect on protein trafficking (Anderson CL et al. Nat Commun. 2014;5:5535). An alteration impacting the same codon, p.H562P, has also been associated with LQTS (Sharma D et al. J Mol Cell Cardiol. 2004;37:79-89). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.91		.;Gain of MoRF binding (P = 0.0578);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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: rs199472922; hg19: chr7-150648796;