rs138498207

chr7-150950195-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP3 BP6 BS2

The NM_000238.4(KCNH2):c.2371C>T(p.Arg791Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,609,838 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. R791Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:5 O:1
• Conservation: PhyloP100: 1.48

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 -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000238.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776
• BP6: Variant 7-150950195-G-A is Benign according to our data. Variant chr7-150950195-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=3}.
• BS2: High AC in GnomAd at 36 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2371C>T	p.Arg791Trp	missense_variant	9/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2371C>T	p.Arg791Trp	missense_variant	9/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes AF: 0.000242 AC: 36 AN: 148782 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000872

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: 0.00

Gnomad OTH AF: 0.000490

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 250940 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135676

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1460954 Hom.: 0 Cov.: 39 AF XY: 0.0000385 AC XY: 28 AN XY: 726816

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000249 AC: 37 AN: 148884 Hom.: 0 Cov.: 30 AF XY: 0.000248 AC XY: 18 AN XY: 72510

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000219

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.0000695 Hom.: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:2 Benign:2

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	Feb 05, 2024	This missense variant replaces arginine with tryptophan at codon 791 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). Functional studies have shown that this variant altered Kv11.1 channel activation and deactivation (PMID: 25417810, 29752375). This variant has been reported in one case of sudden infant death syndrome (PMID: 29752375) and one individual with long QT syndrome (PMID: 31521807 ). This variant has been identified in 25/281704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Long QT syndrome 2 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Pathogenic, no assertion criteria provided	clinical testing	Research Institute, Imperial College London Diabetes Centre	Jan 24, 2021	The KCNH2 p.R791W variant which was detected in the proband, in addition to her father and brother who both have a prolonged QT interval, has been reported previously in one individual with LQTS (PMID: 19716085), and was absent from more than 2,600 control alleles. It is reported in the population databases dbSNP (rs138498207) and Genome Aggregation Database (gnomAD) with a minor allele frequency (MAF) of 0.008875%. This missense mutation is also classified as a variant of uncertain clinical significance in the ClinVar database (Variation ID: 67391). It is located in a highly conserved residue and in silico and bioinformatic analysis (KvSNP, Polyphen2, Single Nucleotide Polymorphisms & Go, and SIFT) predicted this variant to be pathogenic and probably damaging to the protein structure and function. Functional studies by Anderson et al. showed that expression of the KCNH2 p.R791W variant in the absence of a wildtype allele results in normal protein trafficking to the cell membrane, but altered channel gating resulting in dysfunctional channels but with nearly normal values for the repolarizing outward potassium current (IKv11.1) density. On the basis of the genotypes - phenotypes associations in our study, segregation analysis and previous studies mentioned, we classify the p.R791W variant as the putative disease-causative variant that contributes to the LQTS phenotype observed. -

Brugada syndrome 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Research Institute, Imperial College London Diabetes Centre

-

The KCNH2 p.R791W variant which was detected in the proband, has been reported previously in one individual with LQTS (PMID: 19716085), and was absent from more than 2,600 control alleles. It is reported in the population databases dbSNP (rs138498207) and Genome Aggregation Database (gnomAD) with a minor allele frequency (MAF) of 0.008875%. This missense mutation is also classified as a variant of uncertain clinical significance in the ClinVar database (Variation ID: 67391). It is located in a highly conserved residue and in silico and bioinformatic analysis (KvSNP, Polyphen2, Single Nucleotide Polymorphisms & Go, and SIFT) predicted this variant to be pathogenic and probably damaging to the protein structure and function. Functional studies by Anderson et al. showed that expression of the KCNH2 p.R791W variant in the absence of a wildtype allele results in normal protein trafficking to the cell membrane, but altered channel gating resulting in dysfunctional channels but with nearly normal values for the repolarizing outward potassium current (IKv11.1) density. As suggested by Bezzina et al., BrS may not be a monogenic disorder but rather oligogenic and due to multiple susceptibility variants acting in concert via one or more mechanistic pathways that are associated with developing a Brugada syndrome phenotype. This result was interpreted in the clinical context of this patient and on the basis of the genotypes - phenotypes associations in our study, we may speculate that although rare; the LQT2- associated p.R791W variant may not have a direct disease-causative role in BrS but may act as a strong modifier variant that configures the BrS ECG pattern observed in the proband. -

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 tryptophan at codon 791 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). Functional studies have shown that this variant altered Kv11.1 channel activation and deactivation (PMID: 25417810, 29752375). This variant has been reported in one case of sudden infant death syndrome (PMID: 29752375) and one individual with long QT syndrome (PMID: 31521807 ). This variant has been identified in 25/281704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 05, 2024

Variant summary: KCNH2 c.2371C>T (p.Arg791Trp) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain (IPR000595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 281704 control chromosomes, predominantly at a frequency of 0.00093 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Long QT Syndrome phenotype (0.00012), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2371C>T has been reported in the literature in individuals affected with Long QT Syndrome and sudden infant death syndrome (Kapplinger_2009, Smith_2018), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. One functional study showed this variant with competent trafficking and moderate alteration on gating (Anderson_2014) with nearly normal values for the repolarizing outward potassium current density or Ikv11.1. Another functional study demonstrated this variant expressed and generated peak Kv11.1 current levels similar to cells expressing wild-type-Kv11.1 channels but altered gating (Smith_2018). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 25417810, 32048431, 19716085, 29247119, 26332594, 29752375). ClinVar contains an entry for this variant (Variation ID: 67391). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2019

This variant is associated with the following publications: (PMID: 32048431, 19716085, 23861362, 26332594, 25637381, 22581653, 29247119, 25417810, 29752375) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

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:19716085). 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	Pathogenic	0.64
CardioboostArm	Benign	0.0047
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.6	D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.81
MVP		0.94
MPC		2.2
ClinPred		0.51	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs138498207; hg19: chr7-150647283;