chr7-150951738-A-G

Position:

chr7-150951738-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000238.4(KCNH2):c.1655T>C(p.Leu552Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,612,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000052 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 7-150951738-A-G is Pathogenic according to our data. Variant chr7-150951738-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 67225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951738-A-G 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.1655T>C	p.Leu552Ser	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.1655T>C	p.Leu552Ser	missense_variant	7/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251098

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000786

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460014

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

725882

show subpopulations

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:

0.000694

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000377

Hom.:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2023	Published functional studies show p.(L552S) disrupts trafficking and increases the activation and deactivation rates of the potassium channel (Piippo et al., 2000; Anderson et al., 2014); 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: 19716085, 26332594, 10483966, 23098067, 15176425, 25417810, 19841300, 11854117, 15840476, 12477631, 26063740, 23651034, 19160088, 10973849, 22949429, 21244686, 29622001, 10841244, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 29, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Leu552Ser (c.1655T>C) Based on the data reviewed below, we consider it very likely disease causing. This variant has been reported in at least 8 individuals with LQTS in the scientific literature. It is considered a founder mutation in the Finnish population. There is very limited segregation data but one study (Piippo et al. 2000) presented in vitro functional data suggesting this variant increases activation and deactivation rates (see below). This is a non-conservative amino acid substitution in which a nonpolar leucine is replaced with an uncharged polar and small serine at a position that is completely conserved across species (as are neighboring amino acids). In terms of in silico prediction programs, Mutation Taster predicts this variant to be disease causing and PolyPhen predicts probably damaging. The variant occurs in exon 7, which is within the S5 domain of the KCNH2 protein. Mutations in the KCNH2 gene have been reported in approximately 25-35% of patients with autosomal dominant long QT syndrome, and are associated with increased risk of cardiac events triggered by exercise and auditory stimulation (especially during sleep). Variants at nearby residues have been reported in HGMD in association with LQTS (Ala558Glu; Leu559His; Ala561Thr) supporting the functional importance of this region of the protein. There is also a nearby missense variant, p.Gly572Ser, which our team considers to be very likely disease causing. Swan et al. 1999: This L552S variant was identified in one family with LQTS, where the authors vaguely refer to it co-segregating with disease (though they do not include specific numbers). Piippo et al. 2000: Studied two sibs showing prolonged QT and their asymptomatic parents for mutations in the KCNH2 gene. This L552S mutation was identified in heterozygous state in both parents and homozygous state in both severely affected siblings. Authors screened 88 unrelated Finnish probands with LQTS total, identifying this variant in 4 additional families. Thus in total, 6 apparently unrelated families with LQTS were identified with this variant (corresponding to a prevalence rate of 7% among Finnish LQTS families). The mutation was in total identified in 40 individuals across these 6 families and absent from 63 unaffected family members. The authors also performed in vitro functional studies where they transiently expressed L552S in COS7 cells—the mutant displayed a marked increase in both activation and deactivation rates as compared to wild type channels. Absent from 100 controls. Splawski et al. 2000: Screened 262 individuals with LQTS of European ancestry for mutations in 5 LQT genes. All mutations absent from >200 control individuals. This L552S variant was identified in one LQT family in this study. No segregation data was presented. Marjamaa et al. 2009: Genotyped 6,334 subjects over the age of 30 from a population cohort for four Finnish founder mutations (including this KCNH2 variant). The authors state that these four mutations account for up to 70% of the known genetic spectrum of long QT syndrome in Finland. Identified this L552S variant in 2 of 6334 individuals from Finland, where the average QT interval was 442+/- 32 (420-465) in mutation carriers. This variant is identified in several other reviews implicating its role as a Finnish founder mutation (Zhang et al. 2010; Hoffman et al. 2011). In total, this variant is absent from more than 6800 controls derived from publicly available control databases and publications in the scientific literature (including ~6,500 individuals of European and African American descent from the NHLBI Exome Sequencing project; > 200 control indi -

Long QT syndrome 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 27, 2018	This c.1655T>C (p.Leu552Ser) variant in exon 7 of the KCNH2 gene has been reported in a Finnish family with two homozygous Finnish siblings presenting severe phenotype of Long QT syndrome (PMID:10841244). This variant is also reported in heterozygous state in multiple unrelated individuals with Long QT syndrome(PMID: 10483966, 10973849, 19716085, 22949429). Functional study reported this variant caused trafficking deficiency of protein (PMID 25417810). This c.1655T>C(p.Leu552Ser) variant in the KCNH2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 19, 2015	- -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces leucine with serine at codon 552 of the KCNH2 protein. This variant is found within the highly conserved transmembrane S5 domain (aa 548-568). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes KCNH2 protein trafficking deficiency and impairs potassium channel function (PMID: 10841244, 25417810, 32392813). This variant has been described as a founder mutation in the Finnish population, designated as HERG-Fin (PMID: 10841244). It has been reported in 11 Finnish families affected with long QT syndrome (PMID: 10483966, 10841244, 15176425). In these families, 38% of the 90 carriers showed symptoms (PMID: 15176425) and 2 homozygous siblings showed severe phenotypes (PMID: 10841244). The mean QTc interval differed significantly between carriers and non-carriers (p<0.001) (PMID: 10841244). This variant has also been reported in 7 individuals from other populations, who were affected with long QT syndrome (PMID: 10973849, 11854117, Color internal data) or suspected of having long QT syndrome (PMID: 15840476). This variant has been identified in 20/282492 chromosomes (19/25098 Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 552 of the KCNH2 protein (p.Leu552Ser). This variant is present in population databases (rs199472918, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Long QT syndrome in a single family with two affected neonatal homozygotes and long QT syndrome (PMID: 10841244, 10973849, 21244686, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67225). 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: 10841244, 25417810). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The p.L552S pathogenic mutation (also known as c.1655T>C), located in coding exon 7 of the KCNH2 gene, results from a T to C substitution at nucleotide position 1655. The leucine at codon 552 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported to segregate with disease in multiple families with long QT syndrome (LQTS) type 2 and is considered a founder mutation in the Finnish population (Piippo K. et al. 2000 J Am Col Card 35(7) 1919-1925; Fodstad H. et al 2004 Ann Med 36:53-673; Marjamaa A. et al. 2009 Ann Med 41(3):234-240). Two Finnish sisters with more severe LQTS phenotypes were homozygous for p.L522S (Piippo K. et al 2000 J Am Col Card 35(7) 1919-1925). Immunoblot and electrophysiological data along with computational structural models suggest that p.L552S is a protein trafficking deficient mutation (Anderson CL et al. 2014 Nat Commun 5:5535). Based on the supporting evidence, p.L552S is interpreted as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 11, 2023

This missense variant replaces leucine with serine at codon 552 of the KCNH2 protein. This variant is found within the highly conserved transmembrane S5 domain (aa 548-568). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes KCNH2 protein trafficking deficiency and impairs potassium channel function (PMID: 10841244, 25417810, 32392813). This variant has been described as a founder mutation in the Finnish population, designated as HERG-Fin (PMID: 10841244). It has been reported in 11 Finnish families affected with long QT syndrome (PMID: 10483966, 10841244, 15176425). In these families, 38% of the 90 carriers showed symptoms (PMID: 15176425) and 2 homozygous siblings showed severe phenotypes (PMID: 10841244). The mean QTc interval differed significantly between carriers and non-carriers (p<0.001) (PMID: 10841244). This variant has also been reported in 7 individuals from other populations, who were affected with long QT syndrome (PMID: 10973849, 11854117, Color internal data) or suspected of having long QT syndrome (PMID: 15840476). This variant has been identified in 20/282492 chromosomes (19/25098 Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant 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:10483966;PMID:10841244;PMID:10973849;PMID:11854117;PMID:12477631;PMID:12690509;PMID:15840476;PMID:19160088;PMID:19716085;PMID:19841300). 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

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.8

D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.92

MVP

1.0

MPC

2.5

ClinPred

0.84

GERP RS

4.1

Varity_R

0.95

gMVP

0.98

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