Genetic Variant KCNH2:p.Gly601Ser (chr7-150951592-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_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 (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 1.46

Variant links:

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]

KCNH2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000238.4

PM2

Very rare variant in population databases, with high coverage;

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 rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.1801G>A	p.Gly601Ser	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.1801G>A	p.Gly601Ser	missense_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:1

Dec 29, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Pathogenic:1

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 20, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Congenital long 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 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

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Uncertain

0.58

.;D;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

-0.78

.;N;.

PrimateAI

Uncertain

0.57

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over