rs143512106

chr7-150948483-G-Achr7-150948483-G-T

Variant summary

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

The NM_000238.4(KCNH2):c.2653C>T(p.Arg885Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,612,162 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R885H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3 O:1
• Conservation: PhyloP100: 4.89

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, 0.818
• BS2: High AC in GnomAd at 16 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2653C>T	p.Arg885Cys	missense_variant	11/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2653C>T	p.Arg885Cys	missense_variant	11/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1633C>T	p.Arg545Cys	missense_variant	7/11	1
KCNH2	ENST00000684241.1	n.3486C>T		non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 151578 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000382

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000224 AC: 56 AN: 249574 Hom.: 0 AF XY: 0.000266 AC XY: 36 AN XY: 135168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000435

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000100 AC: 146 AN: 1460584 Hom.: 0 Cov.: 37 AF XY: 0.000109 AC XY: 79 AN XY: 726744

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000518

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000106 AC: 16 AN: 151578 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 73992

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000382

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with cysteine at codon 885 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not change the biophysical properties of the protein (PMID: 18222468). This variant has been reported in several individuals affected with or suspected of having long QT syndrome (PMID: 18752142, 19716085, 27920829, 30369311), and in another individual affected with sudden infant death syndrome (PMID: 17210839). One of these individuals also carried a pathogenic splicing variant in the KCNH2 gene that could explain the observed phenotype (PMID: 27920829). This variant has also been identified in 58/280856 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, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 885 of the KCNH2 protein (p.Arg885Cys). This variant is present in population databases (rs143512106, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 17210839, 18752142, 19716085, 27920829, 30369311). ClinVar contains an entry for this variant (Variation ID: 67422). 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 does not substantially affect KCNH2 function (PMID: 18222468). 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. -

Congenital long QT syndrome Benign:1 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:16244680;PMID:17210839;PMID:18752142;PMID:19716085;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Benign, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Aug 08, 2023	Heterozygous variant NM_000238:c.2653C>T (p.Arg885Cys) in the KCNH2 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. An additional variant NM_003098:c.787G>T (p.Ala263Ser) in the SNTA1 gene was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0002065 (Date of access 08-08-2023). Clinvar contains entry for this variant (Variation ID: 67422). This variant has been reported in over a dozen studies in patients with variable phenotypes. Experimental data showed the variant exhibited biophysical properties indistinguishable from WT-HERG (PMID: 18752142). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Benign with following criteria selected: BS1, BS3, PM1, PP2, PP3. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 30, 2018

Variant summary: KCNH2 c.2653C>T (p.Arg885Cys) 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 0.0002 in 275594 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), suggesting the variant may be benign. However, this observation must be interpreted cautiously due to the presence of potenially affected individuals in the ExAC and gnomAD databases. c.2653C>T has been reported in the literature in individuals affected with Arrhythmia without strong evidence for or against pathogenicity. However, one publication reported a co-occurrence with a pathogenic KCNH2 variant (c.1557+1G>C), providing supporting evidence for a benign role (Burns_2016). One publication reports experimental evidence suggesting there is no functional effect of the variant, though the data was not presented for review (Rhodes_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional information becomes available. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 20, 2023

This missense variant replaces arginine with cysteine at codon 885 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not change the biophysical properties of the protein (PMID: 18222468). This variant has been reported in several individuals affected with or suspected of having long QT syndrome (PMID: 18752142, 19716085, 27920829, 30369311), and in another individual affected with sudden infant death syndrome (PMID: 17210839). One of these individuals also carried a pathogenic splicing variant in the KCNH2 gene that could explain the observed phenotype (PMID: 27920829). This variant has also been identified in 58/280856 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

KCNH2: BP2, BS3:Supporting -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostArm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.016	B;D
Vest4		0.72
MVP		1.0
MPC		0.79
ClinPred		0.34	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143512106; hg19: chr7-150645571; COSMIC: COSV51207800; COSMIC: COSV51207800;