NM_000238.4:c.2350C>T

Variant names:

• chr7-150950216-G-A
• rs12720441
• NM_000238.4:c.2350C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1 PP3_Strong PP5 BS2

The NM_000238.4(KCNH2):​c.2350C>T​(p.Arg784Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,406 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 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 O:1
• Conservation: PhyloP100: 1.42

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 7-150950216-G-A is Pathogenic according to our data. Variant chr7-150950216-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14433.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5, not_provided=1}. Variant chr7-150950216-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 35 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2350C>T	p.Arg784Trp	missense_variant	Exon 9 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2350C>T	p.Arg784Trp	missense_variant	Exon 9 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150868 Hom.: 0 Cov.: 30

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251062 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135716

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461538 Hom.: 0 Cov.: 39 AF XY: 0.0000220 AC XY: 16 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150868 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73546

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: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:2

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 784 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 vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 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. -

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 784 of the KCNH2 protein (p.Arg784Trp). This variant is present in population databases (rs12720441, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 11997281, 15840476, 19841300, 22949429). ClinVar contains an entry for this variant (Variation ID: 14433). 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: 11997281, 19172259, 25417810). 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 provided Pathogenic:1

Feb 21, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Pathogenic:1

Dec 17, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 2 Uncertain:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Reclassified - variant of unknown significance Uncertain:1

Apr 23, 2002

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Uncertain:1

May 07, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2350C>T (p.R784W) alteration is located in exon 9 (coding exon 9) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2350, causing the arginine (R) at amino acid position 784 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

May 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 784 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 vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 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. -

KCNH2-related disorder Uncertain:1

Dec 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNH2 c.2350C>T variant is predicted to result in the amino acid substitution p.Arg784Trp. This variant was reported in individuals with long QT syndrome (KCNH2 gene described as HERG, Yang et al. 2002. PubMed ID: 11997281; Tester et al. 2005. PubMed ID: 15840476; Table S2, Giudicessi et al. 2012. PubMed ID: 22949429). Functional analyses suggest that this variant may result in destabilization of the resultant protein and a reduction in channel activity, and authors of one study speculated that this could be a mild variant (Yang et al. 2002. PubMed ID: 11997281; Anderson et al. 2014. PubMed ID: 25417810). However, this variant has also been documented in the general population and in a cohort of asymptomatic individuals with no prior history of cardiovascular events (Table S1, Chen et al. 2018. PubMed ID: 30662450; Lacaze et al. 2021. PubMed ID: 34135346). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Congenital long QT syndrome Other:1

-

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 as associated with Long QT syndrome in the following publications (PMID:11997281;PMID:14760488;PMID:15840476;PMID:19841300). 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	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.7	D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.97
gMVP		0.85

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: rs12720441; hg19: chr7-150647304; COSMIC: COSV51245342;