Variant 7-150951712-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):c.1681G>A(p.Ala561Thr) 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. A561P) has been classified 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: 7.72

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 18 ACMG points.

PM1

In a transmembrane_region Helical; Name=Segment S5 (size 20) in uniprot entity KCNH2_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 chr7-150951712-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 7-150951712-C-T is Pathogenic according to our data. Variant chr7-150951712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951712-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.1681G>A	p.Ala561Thr	missense_variant	7/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.1681G>A	p.Ala561Thr	missense_variant	7/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727136

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

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2024

This variant has also been reported in the heterozgyous and homozygous state in individuals with sudden cardiac death (PMID: 15120823); Published functional studies demonstrate that the p.(A561T) mutant channel expressed in human embryonic kidney cells failed to generate HERG current and causes defective trafficking of the KCNH2 protein to the plasma membrane (PMID: 23303164, 15120823); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28883014, 16432067, 26669661, 27761161, 18441445, 23470493, 8877771, 16379539, 28855170, 10973849, 20197117, 15828882, 10220144, 11222472, 11854117, 15280442, 19716085, 16253912, 27251404, 18808722, 21367833, 32383558, 32600061, 34546463, 31557540, 23303164, 15840476, 15120823) -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala561 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7889573, 10753933, 12354768, 16432067, 18593567, 22949429, 24606995, 24623279). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 23303164, 23470493). ClinVar contains an entry for this variant (Variation ID: 67229). This missense change has been observed in individuals with clinical features of long QT syndrome and congestive heart failure (PMID: 8877771, 10973849, 28855170). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 561 of the KCNH2 protein (p.Ala561Thr). -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2019

The p.A561T pathogenic mutation (also known as c.1681G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1681. The alanine at codon 561 is replaced by threonine, an amino acid with similar properties, and is located in the S5 transmembrane domain. This mutation has been reported in numerous unrelated individuals with long-QT syndrome (LQTS) and was shown to segregate with disease in a family (Dausse E et al. J Mol Cell Cardiol. 1996;28(8):1609-15; Splawski I et al. Circulation. 2000;102(10):1178-85; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Matsa E et al. Eur Heart J. 2011;32(8):952-62). Functional assays have demonstrated that the mutation has a dominant negative effect on protein localization and function (Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102; Chugh SS et al. J Am Coll Cardiol. 2004;43(9):1625-9; Anderson CL et al. Circulation. 2006;113(3):365-73; Mehta A et al. Cardiovasc Res. 2014; 102(3):497-506). In addition, allele-specific knockdown of the mutant allele was able to rescue cardiomyocytes derived from a LQTS patient who was heterozygous for the p.A561T mutation (Matsa E et al. Eur Heart J. 2014;35(16):1078-87). Furthermore, other alterations in the same codon, p.A561P and p.A561V, have also been detected in patients with LQTS (Bellocq C et al. Mol. Pharmacol. 2004 Nov; 66(5):1093-102; Curran ME et al. Cell 1995 Mar; 80(5):795-803). 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:8877771;PMID:10973849;PMID:11222472;PMID:11854117;PMID:15120823;PMID:15840476;PMID:16379539;PMID:16432067;PMID:18441445;PMID:19716085). 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

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

D;D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.92

MutPred

0.91

.;Loss of stability (P = 0.1197);.;

MVP

1.0

MPC

2.1

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.84

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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