rs199472916

chr7-150951793-G-Achr7-150951793-G-Cchr7-150951793-G-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.1600C>T(p.Arg534Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,437,552 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R534S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.66

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr7-150951793-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200728.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 7-150951793-G-A is Pathogenic according to our data. Variant chr7-150951793-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 67220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951793-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1600C>T	p.Arg534Cys	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1600C>T	p.Arg534Cys	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1437552 Hom.: 0 Cov.: 36 AF XY: 0.00000281 AC XY: 2 AN XY: 711300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2020

Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 67220; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant alters the activation and deactivation kinetics, as well as voltage-dependence of inactivation of the potassium channel (Nakajiima et al., 1999); This variant is associated with the following publications: (PMID: 31844156, 10690305, 23303164, 9600240, 15840476, 18441445, 18752142, 19716085, 19694797, 21308345, 22949429, 15545400, 16432067, 11468227, 10987356, 17905336, 19841300, 30847666) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 534 of the KCNH2 protein (p.Arg534Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9600240, 11668638, 18441445, 21308345, 22949429). ClinVar contains an entry for this variant (Variation ID: 67220). 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: 10690305, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2020

The p.R534C pathogenic mutation (also known as c.1600C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1600. The arginine at codon 534 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the S4 domain. This mutation has been detected in several unrelated individuals with long QT syndrome as well as in individuals from multiple LQTS cohorts, and has been reported to segregate with disease in families (Itoh T et al. Hum. Genet., 1998 Apr;102:435-9; Nakajima T et al. Cardiovasc. Res., 1999 Nov;44:283-93; Hayashi K et al. Jpn Heart J, 2000 May;41:399-404; Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14; Ernesto C et al. Arq. Bras. Cardiol., 2011 Mar;96:172-8; Giudicessi JR et al. Circ Cardiovasc Genet, 2012 Oct;5:519-28; Seethala S et al. J Am Heart Assoc, 2015 Dec;4). In addition, in vitro and in vivo functional assays have indicated this variant to result in deficient protein trafficking and/or altered ion channel function (Nakajima T et al. Cardiovasc. Res., 1999 Nov;44:283-93; Anderson CL et al. Circulation, 2006 Jan;113:365-73; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30; Mesquita FCP et al. Sci Rep, 2019 12;9:19203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:9600240;PMID:10690305;PMID:10987356;PMID:11468227;PMID:15840476;PMID:16432067;PMID:16831322;PMID:17905336;PMID:18441445;PMID:18752142;PMID:19716085;PMID:19841300). 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
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.7	D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.055	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.89		.;Gain of helix (P = 0.0128);.;
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
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: rs199472916; hg19: chr7-150648881; COSMIC: COSV51157495;