rs199472990

Positions:

chr7-150950312-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):c.2254C>T(p.Arg752Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,678 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 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.85

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 16 ACMG points.

PM1

In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 7-150950312-G-A is Pathogenic according to our data. Variant chr7-150950312-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 67379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150950312-G-A 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.2254C>T	p.Arg752Trp	missense_variant	9/15	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.2254C>T	p.Arg752Trp	missense_variant	9/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727068

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:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 30, 2021	PS3, PP1_Strong, PM2_supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	Reported in association with LQTS in patients referred for genetic testing at GeneDx and in published literature (Splawski et al., 2000; Ficker et al., 2000; Anderson et al., 2006; Nagaoka et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect on protein trafficking (Ficker et al., 2000; Anderson et al., 2006; Jou et al., 2013); This variant is associated with the following publications: (PMID: 26669661, 11009462, 16432067, 23303164, 27025590, 10973849, 11854117, 18441445, 28607619, 29431731, 26958806, 23098067, 29875689, 30291343, 31447099, 31557540, 34319147, 26582918) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 31, 2013	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.Arg752Trp Based on the case data, strong segregation data, and absence in general population samples, we consider this variant very likely disease causing. This variant has been reported 4 presumably unrelated individuals with long QT syndrome with strong segregation data in one family. Splawski et al (2000) first reported the variant in an individual with LQTS. Ficker et al (2000) also reported the variant in a woman with a history of syncope and sudden death, her extensive family was genotyped and 26 out of 101 individuals were found to harbor the variant. Of these 23 individuals, 17 had a prolonged QT interval and 6 had a history of syncope. Two families with this variant were included in a genotype-phenotype analysis by Moss et al (2002), however given the list of authors, these are likely the same two families reviewed above. Nagaoka et al (2008) also observed this variant in two members of a Japanese family (phenotype for each family member not reported) in their cohort of patients with long QT syndrome. Stattin et al (2012) observed the variant in 1 of 200 unrelated cases referred for long QT genetic testing in their lab in Sweden. Note that the overall yield was 52% so likely a portion of these patients did not in fact have long QT syndrome. Thirty-five patients with this variant were included in a study on individuals from 7 international long QT registries that included probands and family members who carried pathogenic variants (and either did or did not have prolonged QT intervals) (Goldenberg et al 2011). It is unclear how many families this represents and how many of these cases overlap with prior reports such as Splawski et al (2000) and Moss et al (2002), both from the American registry. Functional studies indicate that the mutant protein is not transported to the cell plasma membrane which is where the wild type protein is found (Ficker et al 200, Anderson et al 2006). Other KCNH2 variants associated with long QT have been found to have trafficking defects (ex. p.Phe805Cys, p.Val822Met). PolyPhen2 predicts the variant to be probably damaging. This is a non-conservative amino acid change with a polar Arginine replace with a non-polar Tryptophan. Additional variants in nearby codons (p.Gly749Val, p.Ala753Ser) as well as the same codon (p.Arg752Gln) have been reported in association with long QT. However, p.Arg752Gln was observed in 1 in individual in the NHLBI Exome Sequencing Project (see below). Of note, the reported proband with p.Arg752Gln was homozygous and had severe in utero presentation; in contrast the heterozygotes had no documentable phenotype (Johnson et al 2003). p.Arg752Trp is in the intracellular c-terminal region of the protein. Variants in the transmembrane pore of the channel confer a higher risk of events and a longer QT than variants outside the pore, like this one (Moss et al 2002, Nagaoka et al 2008). In total the variant has not been seen in ~64,400 laboratory controls, published controls and individuals from publicly available population datasets. Splawski et al (2000) did not identify the variant in 200 presumably healthy individuals of unspecified ancestry. GeneDx reports that p.Arg752Trp was absent in 200 Caucasian and African American controls. The variant is not listed in dbSNP or 1000 Genomes. In addition it is not currently listed in the Exome Aggregation Consortium Dataset which includes variant calls on approximately 64,000 individuals of European, African, Asian, and American descent (as of March 1, 2012). -

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2018	Variant summary: KCNH2 c.2254C>T (p.Arg752Trp) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This was functionally supported by the observation of an increased duration of action potential (APD) and lower amplitude of the rapid component (IKr) of the delayed rectifier potassium channel (hERG) observed in induced pluripotent stem cellderived cardiomyocytes (iPSC-CMs) derived from affected patients (Chai_2018). The variant was absent in 276286 control chromosomes (gnomAD). The variant, c.2254C>T, has been reported in the literature in multiple individuals affected with Long QT Syndrome including at-least two LQTS families which segregated with disease (Chai_2018, Nagaoka_2008). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 752 of the KCNH2 protein (p.Arg752Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 11009462, 18441445). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67379). 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: 11009462, 16432067, 23303164). This variant disrupts the p.Arg752 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12621127, 25417810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Congenital long QT syndrome

Pathogenic:1Other: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:10973849;PMID:11009462;PMID:11854117;PMID:16432067;PMID:18441445). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Arg752Trp variant in KCNH2 has been reported in the heterozygous state in at least 5 individuals with long QT syndrome (LQTS; Splawski et al. 2000; Ficker et al. 2000; Nagaoka et al. 2008; Stattin et al. 2012, Itoh et al. 2016), and segregated with disease in 23 individuals in one family (Ficker et al. 2000). In vitro functional studies provide evidence that the p.Arg752Trp variant may impact protein function by causing decreased trafficking to the cell membrane due to its retention in the endoplasmic reticulum (Ficker et al. 2000; Anderson et al. 2006). Additionally, animal models in zebrafish have shown that this variant causes decreased cardiac repolarization (Jou et al. 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 67379), and was absent from large population studies. Other variants at this amino acid position (p.Arg752Gln, Arg752Pro) have been reported in association with LQTS in the Human Gene Mutation Database (HGMD, Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, absence from controls, and functional evidence. The ACMG/AMP criteria applied: PS3_Moderate; PS4_Supporting; PP1_Strong; PM5; PM2; PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The p.R752W pathogenic mutation (also known as c.2254C>T), located in coding exon 9 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2254. The arginine at codon 752 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several individuals with long QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102:1178-85; Ficker E et al. Am J Physiol Heart Circ Physiol. 2000;279:H1748-56; Nagaoka I et al. Circ J. 2008;72:694-9; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95). In addition, this alteration has been shown to impact protein function through trafficking deficiency (Ficker E et al. Am J Physiol Heart Circ Physiol. 2000;279:H1748-56; Anderson CL et al. Circulation. 2006;113:365-73). This alteration is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, another alteration affecting this amino acid (p.R752Q, c.2255G>A) has also been reported in association with LQTS (Johnson WH et al. Pediatr Res. 2003 ;53(5):744-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 27, 2023

This missense variant replaces arginine with tryptophan at codon 752 of the KCNH2 protein. This variant is found within the highly conserved cyclic nucleotide binding region (a.a. 742-842). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that the mutant protein exhibits a severe defect in protein trafficking to the cell surface and very low surface expression compared to the wild type, resulting in the lack of normal potassium channel activity (PMID: 11009462, 16432067, 31557540). Additionally, the mutant protein failed to repolarize in the kcnh2-knockdown embryonic zebra fish (PMID: 23303164). This variant has been reported in at least 7 unrelated individuals affected with long QT syndrome families (PMID: 10973849, 1100946, 11854117, 18441445, 32893267, 33029862). In one of the families, the variant has been identified in 17 individuals affected with long QT syndrome and 6 individuals affected with syncope (PMID: 11009462). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;D;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.6

D;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.93

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

1.8

Varity_R

0.77

gMVP

0.89

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

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