NM_000238.4:c.2948C>T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000238.4(KCNH2):c.2948C>T(p.Thr983Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,612,814 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10B:2O:1

Conservation

PhyloP100: 2.82

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 Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

BS2

High AC in GnomAd4 at 29 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2948C>T	p.Thr983Ile	missense_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 link	c.2948C>T	p.Thr983Ile	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 link	c.1928C>T	p.Thr643Ile	missense_variant	Exon 8 of 11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 link	n.3781C>T		non_coding_transcript_exon_variant	Exon 10 of 13

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000134

AC:

AN:

245588

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

133590

show subpopulations

Gnomad AFR exome

AF:

0.000256

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:

0.000144

Gnomad NFE exome

AF:

0.000235

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1460478

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

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:

0.000189

Gnomad4 NFE exome

AF:

0.000118

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000190

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:10Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jul 05, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr983Ile (ACT>ATT): c.2948 C>T in exon 12 of the KCNH2 (HERG) gene (NM_000238.2). The T983I mutation in the KCNH2 gene has been reported previously in one individual diagnosed with LQTS and it was absent from 1,488 control alleles from individuals of various ethnic backgrounds (Tester D et al., 2005). In addition, the T983I mutation was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. T983I results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The T983 residue is conserved across species. In silico analysis predicts T983I is probably damaging to the protein structure/function. Furthermore, mutations in nearby residues in the C-terminus (P968L, N996I) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein . T983I also has been observed in three other unrelated individuals tested for LQTS at GeneDx.In summary, T983I in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Jun 05, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.2948C>T; p.Thr983Ile variant (rs149955375, ClinVar variant ID 67455) has been identified in at least three patients diagnosed with or referred for testing for long QT syndrome, but no family segregation data has been reported (Miszalski-Jamka 2017, Refsgaard 2012, Tester 2005). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03% (identified on 32 out of 123,742 chromosomes). The threonine at position 983 is moderately conserved, considering 14 species, and computational analyses of the effects of the p.Thr983Ile variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Thr983Ile variant cannot be determined with certainty. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Uncertain:3Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 983 of the KCNH2 protein (p.Thr983Ile). This variant is present in population databases (rs149955375, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 15840476, 23098067, 29957233, 31737537, 32383558, 32893267). ClinVar contains an entry for this variant (Variation ID: 67455). 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: 29957233). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with isoleucine at codon 983 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In an experimental study using genome-editing technology with cardiomyocytes derived from induced human pluripotent stem cells (iPSC-CMs), this variant was demonstrated to cause abnormal electrophysiological profiles suggestive of hallmark LQTS phenotype (PMID: 29957233). However, another study using a high-throughput patch-clamp assay found that this variant does not affect channel function (PMID: 38219013). This variant has been reported in several individuals affected with long QT syndrome (PMID: 15840476, 23098067, 29957233, 32893267) and short QT syndrome (PMID: 23266818), as well as in an individual affected with Andersen Tawil syndrome (PMID: 32843460) who also carried a pathogenic variant KCNJ2 p.Arg218Gln (ClinVar variation ID: 67585). Additionally, it has been identified in a few unaffected individuals (PMID: 22378279, 26746457), and has been reported to not be associated with a prolonged QTc interval in the Icelandic population (PMID: 37449562). This variant occurs at an elevated allele frequency in the general population and has been identified in 40/276956 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Long QT syndrome 2

Pathogenic:1Uncertain:1

Dec 17, 2021

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The genetic variant p.T983I in the KCNH2 gene has also been previously described in databases with conflicting interpretations. Only 40 heterozygous carriers of this variant (and no homozygous cases) are reported in gnomAD with an overall population frequency of 0.0144%. In the Human Genome Mutations Database, the variant is reported as a mutation (HGMD CM055295) The computational interpretation of pathogenicity was controversial (SIFT: tolerated, PolyPhen-2: probably damaging, MutationTaster: disease-causing). However, in 2018, Garg et al. reported a functional study of iPSC-derived cardiomyocytes with the KCNH2 p.T983I variant obtained from a patient with QTc prolongation and a history of presyncope. Patch-clamp revealed prolongation of action potential duration and reduced rapidly-activating delayed rectifier K+ current (IKr) density in T983I-cardiomyocytes. Our patient’s phenotype is consistent with that in the study, and the results of this functional study allow us to classify the p.T983I variant as likely pathogenic. -

May 02, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1

Dec 03, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.Thr983Ile Given the weak case data and the presence in the general population, we consider this a variant of uncertain significance. We could find three reports of this variant that may be associated with phenotype, though unfortunately phenotypic details are either unavailable or unclear. Dr. Ackerman's group reported the variant in one of 541 patients referred to his lab for genetic testing for long QT syndrome. It is unclear if all of these patients had a diagnosis of long QT (Tester et al 2005). Individual phenotypic data is not provided. For the patients with a variant in KCNH2 identified the QTc was over 480 ms in 66% and the Schwartz score was >= 4 in 39%. Ancestry and segregation are not provided. I found two reports online, presumably from the same group, written in Russian, that appear to report this variant in a patient with short QT syndrome (http://www.defibrillation.ru/download/Annaly_aritmologii,2010,1,62-69.pdf and http://arrhythmology.pro/files/pdf/AA_04_2008_full.pdf). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.656). The threonine at codon 983 is conserved across species, as are neighboring amino acids. The only nearby variant I could find was p.Asn985Ser, which has reportedly been reported in association with Brugada syndrome. In total the variant has been seen in 4 of 7818 published controls and individuals from publicly available population datasets.The variant was reported online in 2 of 4297 Caucasian individuals and 1 of 2201 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of July 3rd, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is listed in dbSNP (rs149955375) with submissions from ESP/exome chip, ClinSeq (1 of 570 individuals(Ng et al 2013)), and a locus specific database. The variant was not observed in the following laboratory and published control samples: 750 control individuals (Tester et al 2005). -

Cardiac arrhythmia

Uncertain:1

Apr 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with isoleucine at codon 983 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In an experimental study using genome-editing technology with cardiomyocytes derived from induced human pluripotent stem cells (iPSC-CMs), this variant has been shown to cause abnormal electrophysiological profiles suggestive of hallmark LQTS phenotype (PMID: 29957233). This variant has been reported in several individuals affected with long QT syndrome (PMID: 15840476, 23098067, 29957233, 32383558, 32893267) and short QT syndrome (PMID: 23266818), as well as in unaffected individuals (PMID: 22378279, 26746457). This variant has also been reported in heterozygous state with a pathogenic variant KCNJ2 p.Arg218Gln (ClinVar variation ID: 67585) in an individual affected with Andersen Tawil syndrome (PMID: 32843460). This variant occurs at an elevated allele frequency in the general population and has been identified in 40/276956 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Oct 26, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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:15840476;PMID:22378279). 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

0.12

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.2

.;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.75

N;N

REVEL

Pathogenic

0.74

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.063

T;T

Polyphen

0.99

D;D

Vest4

0.73

MVP

0.94

MPC

0.27

ClinPred

0.18

GERP RS

4.8

Varity_R

0.12

gMVP

0.68

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