rs199473505

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

The NM_000238.4(KCNH2):c.982C>T(p.Arg328Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,614,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00042 ( 3 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8O:1

Conservation

PhyloP100: 3.28

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 Benign. Variant got -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0545232).

BS2

High AC in GnomAd4 at 93 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.982C>T	p.Arg328Cys	missense_variant	Exon 5 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.982C>T	p.Arg328Cys	missense_variant	Exon 5 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000532957.5 link	n.1205C>T		non_coding_transcript_exon_variant	Exon 5 of 9	2
KCNH2	ENST00000684241.1 link	n.1815C>T		non_coding_transcript_exon_variant	Exon 3 of 13

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000570

AC:

143

AN:

250832

Hom.:

AF XY:

0.000560

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00453

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000417

AC:

609

AN:

1461806

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

282

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00412

Gnomad4 NFE exome

AF:

0.000317

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000610

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00555

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000527

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2Other:1

Jan 06, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple unrelated individuals with LQTS (PMID: 19716085, 11334843, 15840476, 16922724, 22949429, 23347029); Reported in an individual who developed Torsades de Pointes in the context of postpartum respiratory distress, left ventricular dysfunction, and a prolonged QT interval while being treated with multiple medications; several relatives who were also found to harbor this variant, including the patient's identical twin, had no clinical evidence of LQTS, leading authors to conclude this patient's arrhythmia likely resulted from multiple factors (PMID: 16720674); Functional studies are inconsistent regarding the effect of this variant on channel function (PMID: 16253915, 11334843, 16432067); 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: 23303164, 16432067, 17275752, 22949429, 23347029, 11334843, 14760488, 15840476, 16922724, 19841300, 28988457, 31737537, 37614113, 37199999, 19716085, 16720674, 16253915) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH2: PP2, BS1 -

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 in the following publications (PMID:11334843;PMID:14760488;PMID:15840476;PMID:16253915;PMID:16432067;PMID:16720674;PMID:16922724;PMID:17275752;PMID:19716085;PMID:19841300). -

Nov 15, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Given the weak case data and presence in population controls, we consider this variant likely benign. One possibility is that this variant contributes to an arrhythmic phenotype, perhaps behaving as a modifier, but not be the primary driver. This is based on the fact that several of the reported cases involved either a more convincing pathogenic variant or QT-prolonging medication, several other reported cases are from cohorts that include individuals who do not have long QT, and the variant is present in individuals not selected for a long QT phenotype, with ~1% of one such cohort having the variant. This is a previously reported variant in the N-terminal region. To date, the reported cases include - drug-induced long QT, complete AV block and Torsades: 2 - patients referred for long QT genetic testing, 25-50% likely don't have long QT: 6 - patients with long QT, all major genes analyzed with no other variants: 4 - patients with long QT and another, high confidence variant: 1 - patient with prolonged QT in the setting of evidence of arrhythmogenic right ventricular cardiomyopathy and a PKP2 frameshift variant: 1 Comparing frequencies: - 4/2500 in Kapplinger series (0.16%) - 64/60,618 in ExAC (0.11%) - 38/3189 Finnish in ExAC (1.2%) -162/141,162 in gnomAD (0.11%); -115/13031 Finnish in gnomAD (0.88%) Chevalier et al (2001) reported the variant in association with what the authors described as acquired long QT syndrome. They found the variant in 1 of 16 cases. The individual with the variant was a 45yo male with no prior medical history of family history of sudden death. He was hospitalized for recent syncopal episodes. An ECG at admission showed QT prolongation and complete AV block, he was diagnosed with "Torsades de pointes" complicating an AV bock and a pacemaker was placed and the QT interval returned to normal once he was paced. Tester et al (2005) observed the variant in 2 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). Millat et al (2006) reported the variant in 3 of 44 unrelated individuals from their French cohort with long QT syndrome with QTc intervals ranging from 483 to 540 ms. No segregation data was provided. They analyzed 5 long QT genes. Hinterseer et al (2006) reported the variant in a 25yo woman who suffered Torsades de Pointes in the setting of transiently impaired LV function, acute respiratory distress syndrome, transient hypokalaemia and QT-prolonging drugs, with a QTc of 485-510 ms. Once her status had normalized and QT-prolonging drugs had been discontinued her QTc was 430 ms and a Dl-sotalol challenge evoked a QTc of 515 ms, which the authors felt was suggestive of a latent susceptibility to QT-prolonging drugs. Four other family members were found to have the variant, "all without clinical manifestations of LQTS". The variant was reported in 4 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Stattin et al (2012) analyzed 5 long QT genes in 200 unrelated long QT patients from their Swedish cohort and identified this variant in one individual. Hedley et al (2013) report -

Long QT syndrome

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2015

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Long QT syndrome 2

Uncertain:1

Apr 27, 2017

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

Benign:1

Nov 10, 2015

Blueprint Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

May 06, 2020

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. -

KCNH2-related disorder

Benign:1

Jun 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiac arrhythmia

Benign:1

Nov 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.055

T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.1

D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0040

D;.

Sift4G

Benign

0.12

T;T

Polyphen

1.0

D;.

Vest4

0.87

MVP

0.99

MPC

2.4

ClinPred

0.14

GERP RS

4.8

Varity_R

0.20

gMVP

0.77

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