rs149955375

chr7-150947623-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:2 O:1
• Conservation: PhyloP100: 2.82

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• BS2: High AC in GnomAd at 29 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2948C>T	p.Thr983Ile	missense_variant	12/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2948C>T	p.Thr983Ile	missense_variant	12/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1928C>T	p.Thr643Ile	missense_variant	8/11	1
KCNH2	ENST00000684241.1	n.3781C>T		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152220 Hom.: 0 Cov.: 33

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: 33 AN: 245588 Hom.: 0 AF XY: 0.000142 AC XY: 19 AN XY: 133590

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.: 0 Cov.: 36 AF XY: 0.0000991 AC XY: 72 AN XY: 726534

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: 29 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74484

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.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	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). 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. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	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. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	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). -

Long QT syndrome 2 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Dec 17, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 02, 2019	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

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Dec 03, 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.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

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 03, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

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

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: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
CardioboostArm	Benign	0.012
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	0.85	D;D;D
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs149955375; hg19: chr7-150644711;