7-150951592-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000238.4(KCNH2):c.1801G>A(p.Gly601Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G601C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.46

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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr7-150951591-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200730.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 7-150951592-C-T is Pathogenic according to our data. Variant chr7-150951592-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951592-C-T is described in Lovd as [Pathogenic]. Variant chr7-150951592-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1801G>A	p.Gly601Ser	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1801G>A	p.Gly601Ser	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461868 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: 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

Blueprint Genetics

Dec 29, 2014

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 601 of the KCNH2 protein (p.Gly601Ser). 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: 9452080, 10862094, 18441445, 18752142, 19841300). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67279). 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 tolerated. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 10226095, 12775586, 23303164). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2020

The p.G601S pathogenic mutation (also known as c.1801G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1801. The glycine at codon 601 is replaced by serine, an amino acid with similar properties, and is located in the S5/pore region. This variant has been described in multiple patients with long QT syndrome (Akimoto K et al. Hum Mutat. 1998;Suppl 1:S184-6; Swan H et al. J Am Coll Cardiol. 1999;34(3):823-9; Splawski I et al. Circulation. 2000;102(10):1178-85; Nagaoka I et al. Circ J. 2008;72(5):694-9; Giudicessi JR et al. Circ Cardiovasc Genet. 2012;5(5):519-28). In several functional in vivo and in vitro analyses, this variant adversely affected the potassium ion channel, resulting in deficient protein trafficking and repolarization (Furutani M et al. Circulation. 1999;99(17):2290-4; Ficker E et al. J Biol Chem. 2002;277(7):4989-98; Jou CJ et al. Circ Res. 2013;112(5):826-30). In addition, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Wang W et al. Cell. 2017 04;169(3):422-430.e10). 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:9452080;PMID:10483966;PMID:10862094;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19716085;PMID:19841300;PMID:21490315;PMID:21573751;PMID:10226095;PMID:11741928). 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	Benign	0.076
CardioboostArm	Benign	0.000026
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Benign	23
Dann	Benign	0.80
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	0.75	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.15	N;N;.
REVEL	Uncertain	0.63
Sift	Benign	0.64	T;T;.
Sift4G	Benign	0.86	T;T;T
Polyphen		0.026	B;B;.
Vest4		0.54
MutPred		0.80		.;Gain of glycosylation at G601 (P = 0.0247);.;
MVP		1.0
MPC		1.1
ClinPred		0.63	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.82

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: rs199472936; hg19: chr7-150648680; COSMIC: COSV51209384;