rs141401803

Positions:

chr7-150947711-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_000238.4(KCNH2):c.2860C>T(p.Arg954Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 1,580,214 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 1.38

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

BS2

High AC in GnomAd4 at 6 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2860C>T	p.Arg954Cys	missense_variant	12/15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 link	c.2860C>T	p.Arg954Cys	missense_variant	12/15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 link	c.1840C>T	p.Arg614Cys	missense_variant	8/11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 link	n.3693C>T		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152156

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000375

AC:

AN:

186632

Hom.:

AF XY:

0.0000390

AC XY:

AN XY:

102580

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000349

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000385

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000629

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000476

AC:

AN:

1428058

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

708030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000249

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000484

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000556

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

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:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000255

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 14, 2024	This missense variant replaces arginine with cysteine at codon 954 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown this variant may reduce ionic current and accelerate channel deactivation (PMID: 17210839, 18222468, 18675227). This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839), drug-induced QT prolongation (PMID: 18675227), atrial fibrillation (Han et al., 2010), sudden unexplained death (PMID: 27930701), and sudden death suspected of being an inherited arrhythmogenic syndrome (PMID: 32268277). This variant has also been identified in 8/217960 chromosomes in the general population 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 954 of the KCNH2 protein (p.Arg954Cys). This variant is present in population databases (rs141401803, gnomAD 0.005%). This missense change has been observed in individuals with KCNH2-related conditions and/or Long QT (PMID: 17210839, 18675227, 27930701; Invitae). ClinVar contains an entry for this variant (Variation ID: 67444). 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: 17210839, 18222468, 18675227). This variant disrupts the p.Arg954 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 27026747), which suggests that this may be a clinically significant amino acid residue. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 17, 2024

Variant summary: KCNH2 c.2860C>T (p.Arg954Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 186996 control chromosomes. c.2860C>T has been reported in the literature in individuals affected with clinical features of KCNH2-related conditions, including SIDS (e.g., Arnestad_2007) and drug-induced arrhythmia and/or prolonged QT (e.g, Biliczki_2008, Behr_2013). These data indicate that the variant may be associated with disease. At least two publications suggest the variant inhibits biophyisical properties (e.g., Biliczki_2008, Rhodes_2008). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 18222468, 18675227, 24223155). ClinVar contains an entry for this variant (Variation ID: 67444). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2022

Observed in individuals with sudden infant death syndrome (SIDS) or sudden unexpected death (SUD) (Arnestad et al., 2007; Sanchez et al., 2016); Also reported in an individual with an increased QTc interval during macrolide treatment that normalized after drug withdrawal, as well as in her daughter who had a QTc of approximately 450ms (Biliczki et al., 2008); Published functional studies demonstrate a damaging effect as this variant results in reduced channel current and significant alterations in channel biophysical properties (Rhodes et al., 2008; Biliczki et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21778721, 23304551, 24223155, 21215473, 28316956, 26633542, 27026747, 18675227, 27930701, 34502138, 22581653, 32048431, 32268277, 17210839, 31043699, 18222468) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2019

The c.2860C>T (p.R954C) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2860, causing the arginine (R) at amino acid position 954 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 20, 2023

This missense variant replaces arginine with cysteine at codon 954 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown this variant may reduce ionic current and accelerate channel deactivation (PMID: 17210839, 18222468, 18675227). This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839), drug-induced QT prolongation (PMID: 18675227), and atrial fibrillation (Han et al., 2010). This variant has also been identified in 8/217960 chromosomes in the general population 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. -

SUDDEN INFANT DEATH 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 Sudden infant death syndrome in the following publications (PMID:17210839;PMID:18675227). 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

0.11

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

.;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.69

.;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.5

N;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.10

T;T

Polyphen

1.0

D;D

Vest4

0.60

MVP

0.99

MPC

0.62

ClinPred

0.22

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

Varity_R

0.18

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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