chr7-150974920-T-G

Position:

• chr7-150974920-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000238.4(KCNH2):​c.98A>C​(p.Asn33Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 O:1
• Conservation: PhyloP100: 7.88

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.98A>C	p.Asn33Thr	missense_variant	2/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.98A>C	p.Asn33Thr	missense_variant	2/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.321A>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2023	This missense change has been observed in individual(s) with KCNH2-related conditions (PMID: 10973849, 11854117, 23174487, 23631430, 28087566). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 10187793, 21536673, 22396785, 23303164, 25417810, 29725305, 31557540). 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. ClinVar contains an entry for this variant (Variation ID: 67553). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 33 of the KCNH2 protein (p.Asn33Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2018	Variant summary: KCNH2 c.98A>C (p.Asn33Thr) results in a non-conservative amino acid change in the in the PAS domain of the encoded voltage-gated potassium channel that is involved in the regulation of the slow deactivation kinetics (Gianulis 2011). Five of five in-silico tools predict a damaging effect of the variant on protein function. The effect of the variant on protein function was assessed in several in vitro functional studies. KCNH2 dysfunction can occur through a number of mechanisms, including defects in ion permeation, channel opening and closing (gating) or protein trafficking (Gianulis 2011). The variant protein had similar trafficking to the wild type (Harley 2012, Anderson 2014), and also exhibited robust currents when studied in Xenopus oocytes or HEK293 cells. However, the channel deactivation kinetics was significantly accelerated, that might result in prolongation of the ventricular action potential and predispose affected individuals to arrhythmias (Chen 1999, Gianulis 2011). An in vivo functional study performed in a zebrafish model, also supported the pathogenicity of the variant protein by demonstrating a repolarization-deficient phenotype (Jou 2013). Though one study reported the variant to be found in 1/187 Caucasian control individuals, suggesting that it may be a benign polymorphism (Ackerman 2003), the variant allele was not found in large control populations (ExAC and gnomAD) or in healthy controls tested in other studies (Splawski 2000, Lieve 2013). c.98A>C has been reported in the literature in several individuals affected with LQTS (Splawski 2000, Moss 2002, Shimizu 2009, Mullally 2013, Lieve 2013), and also was found in one patient diagnosed with Sudden Cardiac Death (Seidelmann 2017). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 30, 2024	This missense variant replaces asparagine with threonine at codon 33 in the N-terminal PAS domain of the KCNH2 protein. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have not conclusively demonstrated mechanism of disease of this variant but generally indicate that this variant results in the altered kinetics of the potassium channel activity and reduced protein expression (PMID: 10187793, 22396785, 23303164, 26958806, 29725305, 31557540, 34801551). This variant has been reported in over ten individuals affected with long QT syndrome (PMID: 10973849, 11854117, 19926013, 23174487, 23631430), in an individual with sudden cardiac death (PMID: 28087566), and in a few unaffected individuals (PMID: 14661677, 19841300, 22949429). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	Reported in association with LQTS and sudden cardiac death (PMID: 10187793, 11854117, 19926013, 23174487, 28087566, 10973849); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate p.(N33T) causes defective potassium channel gating in vitro and a repolarization-deficient phenotype in a zebrafish model (PMID: 10187793, 21536673, 22396785, 31557540, 23303164, 26958806); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14661677, 22949429, 25417810, 22396785, 21536673, 11854117, 23174487, 19926013, 23631430, 10187793, 31557540, 19841300, 28087566, 29725305, 32475984, BayeJ2022, 10973849, 34801551, 23303164, 37187232, 35688148, 26958806) -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:10187793;PMID:10973849;PMID:11854117;PMID:14661677;PMID:19841300;PMID:21536673;PMID:22396785). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The p.N33T variant (also known as c.98A>C), located in coding exon 2 of the KCNH2 gene, results from an A to C substitution at nucleotide position 98. The asparagine at codon 33 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in long QT syndrome and sudden cardiac death cohorts (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:). This alteration has also been reported in control cohorts (Ackerman MJ et al. Mayo Clin Proc, 2003 Dec;78:1479-87; Kapa S et al. Circulation, 2009 Nov;120:1752-60). This variant has been studied in numerous functional settings with a possible impact on protein function (Gianulis EC et al. J Biol Chem, 2011 Jun;286:22160-9; Jou CJ et al. Circ Res, 2013 Mar;112:826-30; Perry MD et al. J Physiol, 2016 Jul;594:4031-49; Ng CA et al. Heart Rhythm, 2020 Mar;17:492-500). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.051	B
Vest4		0.95
MutPred		0.92		Gain of methylation at K28 (P = 0.1107);
MVP		0.96
MPC		1.6
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.81
gMVP		0.99

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: rs199473487; hg19: chr7-150672008;