7-150948984-C-T

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.2464G>A(p.Val822Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V822A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 7.90

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr7-150948983-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2575020.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 7-150948984-C-T is Pathogenic according to our data. Variant chr7-150948984-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948984-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2464G>A	p.Val822Met	missense_variant	10/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2464G>A	p.Val822Met	missense_variant	10/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1444G>A	p.Val482Met	missense_variant	6/11	1
KCNH2	ENST00000684241.1	n.3297G>A		non_coding_transcript_exon_variant	8/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 02, 1996

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2022

Reported in association with LQTS in multiple families (Berthet et al., 1999; Satler et al.,1996; Benhorin et al., 2002; Kapplinger et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as cell lines with this variant showed no voltage and showed defects in biosynthetic processing of KCNH2 (HERG) channels as the protein was retained in the endoplasmic reticulum (Zhou et al., 1998; Anderson et al., 2006); 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: 12716119, 23303164, 12354768, 11278781, 11844290, 16432067, 10086971, 19716085, 11854117, 31557540, 8914737, 15840476, 30244407, 9694858) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2022

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 822 of the KCNH2 protein (p.Val822Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome and long QT syndrome (PMID: 8914737, 10086971, 10973849, 11854117, 15840476, 15851119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14424). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 9694858, 11278781, 23303164). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2018

The p.V822M pathogenic mutation (also known as c.2464G>A), located in coding exon 10 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2464. The valine at codon 822 is replaced by methionine, an amino acid with highly similar properties. This alteration was originally described to co-segregate with long QT syndrome in multiple individuals in a large family (Satler CA et al. Am J Med Genet. 1996;65(1):27-3). Subsequently, this mutation has been reported in multiple patients with long QT (Berthet M et al. Circulation. 1999;99(11):1464-70; Lupoglazoff JM et al. Circulation. 2001;103(8):1095-101; Moss AJ et al. Circulation. 2002;105(7):794-9;Tester DJ et al. Heart Rhythm 2005;2(5):507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This alteration is located in the C-terminal region of the KCNH2 gene, and functional in vitro and in vivo analyses have demonstrated deficient protein trafficking and repolarization related to a loss of function effect (Zhou Z et al. J Biol Chem. 1998;273(33):21061-6; Anderson CL et al. Circulation. 2006;113(3):365-73. Jou CJ et al. Circ Res. 2013;112(5):826-30). Based on the supporting evidence, p.V822M is interpreted as a disease-causing mutation. -

Long QT syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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:8914737;PMID:10086971;PMID:11222472;PMID:11854117;PMID:15840476;PMID:16432067;PMID:19716085;PMID:9694858). 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	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.88		.;Gain of catalytic residue at V822 (P = 0.0504);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.95

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: rs121912506; hg19: chr7-150646072;