rs199473522

chr7-150951583-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.1810G>A(p.Gly604Ser) 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. G604D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.79

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 9 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 chr7-150951582-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200741.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 7-150951583-C-T is Pathogenic according to our data. Variant chr7-150951583-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951583-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1810G>A	p.Gly604Ser	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1810G>A	p.Gly604Ser	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 604 of the KCNH2 protein (p.Gly604Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (LQT) (PMID: 10220144, 10973849, 11854117, 12566525, 14998624, 17171344, 18441445, 19843919, 22402334, 22821100, 22949429, 23158531). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67281). 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: 18386051, 25417810). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

Reported multiple times in association with LQTS (Jongbloed et al., 1999; Splawski et al., 2000; Van Langen et al., 2003; Lupoglazoff et al., 2004; Tester et al., 2005; Nagaoka et al., 2008; Sato et al., 2012; Kauferstein et al., 2017); Published functional studies have demonstrated that G604S causes loss of function of the potassium channel in a dominant negative manner (Huo et al., 2008; Anderson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic (ClinVar Variant ID 67281; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25417810, 18441445, 26847485, 28741726, 22821100, 10973849, 23158531, 19843919, 10220144, 18386051, 15840476, 11854117, 17171344, 19716085, 19841300, 22402334, 22949429, 27199074, 28316956, 12566525, 14998624, 28516454, 28472724, 31557540, 32661217, 31737537, 32940533) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2020

The c.1810G>A (p.G604S) alteration is located in coding exon 7 of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 1810, causing the glycine (G) at amino acid position 604 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the KCNH2 c.1810G>A alteration was not observed, with coverage at this position. The c.1810G>A (p.G604S) alteration has been detected in multiple unrelated individuals reported to have confirmed or suspected long QT syndrome (Jongbloed, 1999; Splawski, 2000; Van Langen, 2003; Lupoglazoff, 2004; Tester, 2005; Tan, 2006; Giudicessi, 2012; Ildarova, 2012; Sato, 2012). This alteration was also reported to segregate with long QT syndrome in multiple affected members of a family (Zhang, 2007). The p.G604 amino acid is conserved in available vertebrate species. In vitro functional studies have reported this alteration to result in abnormal ion channel function and a dominant negative effect on protein trafficking (Huo, 2008; Anderson, 2014). The p.G604S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as 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:10220144;PMID:10973849;PMID:11854117;PMID:12566525;PMID:14998624;PMID:15840476;PMID:17171344;PMID:18386051;PMID:18441445;PMID:19716085;PMID:19841300;PMID:22402334). 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	0.83
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.80		.;Loss of catalytic residue at G604 (P = 0.0292);.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.87

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: rs199473522; hg19: chr7-150648671;