rs199472901

chr7-150952675-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000238.4(KCNH2):c.1307C>T(p.Thr436Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T436T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 1.23

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000238.4
• BS2: High AC in GnomAd at 6 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1307C>T	p.Thr436Met	missense_variant	6/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1307C>T	p.Thr436Met	missense_variant	6/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251460 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	Feb 05, 2024	This missense variant replaces threonine with methionine at codon 436 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). Functional studies have reported the mutant protein to exhibit normal function (PMID: 16432067, 23303164, 34002542). although one study has indicated that this variant alters potassium channel function (PMID: 26129877). This variant has been identified in an individual affected with long QT syndrome (PMID: 9927399), in an individual affected with Romano-Ward syndrome (PMID: 10973849), and in an individual affected with epilepsy (PMID: 34002542). This variant has been identified in 9/282850 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	Invitae	Jan 21, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 436 of the KCNH2 protein (p.Thr436Met). This variant is present in population databases (rs199472901, gnomAD 0.01%). This missense change has been observed in individuals with long QT syndrome (PMID: 9927399; Invitae). ClinVar contains an entry for this variant (Variation ID: 67184). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNH2 function (PMID: 16432067, 23303164, 26129877, 34002542). 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2020

Reported in association with LQTS and atrial fibrillation (Priori et al., 1999; Hayashi et al., 2015); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67184; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Functional studies to date have not yielded consistent conclusions about the effect of this variant on protein function (Anderson et al., 2006; Jou et al., 2013; Hayashi et al., 2015); This variant is associated with the following publications: (PMID: 16432067, 9927399, 26129877, 23303164, 11854117, 10973849) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2022

The c.1307C>T (p.T436M) alteration is located in exon 6 (coding exon 6) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 1307, causing the threonine (T) at amino acid position 436 to be replaced by a methionine (M). 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

Apr 07, 2023

This missense variant replaces threonine with methionine at codon 436 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). Functional studies have reported the mutant protein to exhibit normal function (PMID: 16432067, 23303164, 34002542). although one study has indicated that this variant alters potassium channel function (PMID: 26129877). This variant has been identified in an individual affected with long QT syndrome (PMID: 9927399), in an individual affected with Romano-Ward syndrome (PMID: 10973849), and in an individual affected with epilepsy (PMID: 34002542). This variant has been identified in 9/282850 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. -

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:9927399;PMID:11854117;PMID:16432067). 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	0.091
CardioboostArm	Benign	0.0068
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	23
Dann	Benign	0.97
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.46	N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.46
MutPred		0.76		.;Loss of glycosylation at T436 (P = 0.0445);.;
MVP		1.0
MPC		1.2
ClinPred		0.063	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.60

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

Other links and lift over

dbSNP: rs199472901; hg19: chr7-150649763; COSMIC: COSV100060568;