7-150951629-G-C

Variant names:

• chr7-150951629-G-C
• rs104894021
• NM_000238.4:c.1764C>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000238.4(KCNH2):​c.1764C>G​(p.Asn588Lys) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N588D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.270

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

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_000238.4 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 14437
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr7-150951631-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67266.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to Brugada syndrome, long QT syndrome, short QT syndrome, short QT syndrome type 1, long QT syndrome 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 7-150951629-G-C is Pathogenic according to our data. Variant chr7-150951629-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1764C>G	p.Asn588Lys	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1764C>G	p.Asn588Lys	missense_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short QT syndrome type 1 Pathogenic:1

Apr 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

Jul 26, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N588K variant (also known as c.1764C>G), located in coding exon 7 of the KCNH2 gene, results from a C to G substitution at nucleotide position 1764. The asparagine at codon 588 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals with short QT syndrome (SQTS) (Brugada R et al. Circulation, 2004 Jan;109:30-5; Hong K et al. J Cardiovasc Electrophysiol, 2005 Apr;16:394-6; Akdis D et al. Europace, 2018 Jun;20:f113-f121). In multiple assays testing KCNH2 function, this variant showed functionally abnormal results (Brugada R et al. Circulation, 2004 Jan;109:30-5; Grunnet M et al. Cell Physiol Biochem, 2008 Dec;22:611-24; McPate MJ et al. J Physiol Pharmacol, 2009 Mar;60:23-41; Adeniran I et al. PLoS Comput Biol, 2011 Dec;7:e1002313). In addition, a different alteration located at the same position, resulting in the same protein change, c.1764C>A (p.N588K), has been detected in individuals with SQTS (Brugada R et al. Circulation, 2004 Jan;109:30-5; Suzuki H et al. Pediatr Int, 2014 Oct;56:774-6). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic for KCNH2-related SQTS; however, its clinical significance for KCNH2-related long QT syndrome is uncertain. -

Short QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Short QT syndrome in the following publications (PMID:14676148;PMID:15828882;PMID:19088443;PMID:19439805;PMID:19501051;PMID:22194679). 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	0.78
CardioboostArm	Benign	0.0021
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.65	.;N;.
PhyloP100		0.27
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Uncertain	0.60
Sift	Benign	0.59	T;T;.
Sift4G	Benign	0.78	T;T;T
Polyphen		0.014	B;B;.
Vest4		0.82
MutPred		0.89		.;Gain of ubiquitination at N588 (P = 0.0325);.;
MVP		0.91
MPC		2.0
ClinPred		0.75	D
GERP RS		4.3
Varity_R		0.45
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs104894021; hg19: chr7-150648717;