7-150951495-T-C

Variant names:

• chr7-150951495-T-C
• rs199472961
• NM_000238.4:c.1898A>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.1898A>G​(p.Asn633Ser) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N633D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.86

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Extracellular (size 5) in uniprot entity KCNH2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951496-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 7-150951495-T-C is Pathogenic according to our data. Variant chr7-150951495-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 67323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951495-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1898A>G	p.Asn633Ser	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1898A>G	p.Asn633Ser	missense_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified several unrelated individuals from different ethnic backgrounds with LQTS in published literature (Satler et al., 1998; Lupoglazoff et al., 2001; Nemec et al., 2003; Khositseth et al., 2004; Tester et al., 2005; Tan et al., 2006; Nagaoka et al., 2008; Berge et al., 2008; Kapa et al., 2009; Itoh et al., 2010; Giudicessie et al., 2012; Christiansen et al., 2014; Itoh et al., 2016; Izumi et al., 2016) and referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest that this variant impairs proper KCNH2 channel trafficking and channel function (She et al., 2006; Anderson et al., 2014; Ng et al., 2019); 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: 18752142, 17088455, 18441445, 16842670, 22949429, 9544837, 11222472, 15840476, 26669661, 27041096, 24606995, 23158531, 20541041, 19841300, 15851119, 12877697, 32940533, 31557540, 25417810, 31737537) -

Mar 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PP4, PM1, PM2, PS3_supporting, PS4 -

Long QT syndrome 2 Pathogenic:1

Nov 27, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Pathogenic:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 633 of the KCNH2 protein (p.Asn633Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9544837, 17088455, 19996378, 22949429). ClinVar contains an entry for this variant (Variation ID: 67323). 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: 25417810). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jun 22, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N633S pathogenic mutation (also known as c.1898A>G), located in coding exon 7 of the KCNH2 gene, results from an A to G substitution at nucleotide position 1898. The asparagine at codon 633 is replaced by serine, an amino acid with highly similar properties. This alteration has been previously reported in a number of individuals with long QT syndrome (LQTS) (Satler CA et al. Hum Genet. 1998;102:265-72; Tan HL et al. Circulation. 2006;114:2096-103; Nagaoka I et al. Circ J. 2008;72:694-9; Berge KE et al. Scand J Clin Lab Invest. 2008;68:362-8; Kapa S et al. Circulation. 2009;120:1752-60; Christiansen M et al. BMC Med. Genet. 2014;15:31). In functional in vitro analyses, this variant has been suggested to affect the potassium channel current (She HR et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2006;34:523-7; Ng CA et al. Heart Rhythm. 2020 03;17(3):492-500; Perry MD et al. Cardiovasc Res. 2020 07;116(8):1434-1445) and to cause protein trafficking deficiency (Anderson CL et al. Nat Commun. 2014;5:5535; O'Hare BJ et al. Circ Genom Precis Med. 2020 10;13(5):466-475). Based on internal structural analysis, this variant is predicted to be structurally destabilizing (Liu J et al. J Gen Physiol. 2002 Nov;120(5):723-37; Butler A et a. Front Pharmacol. 2019 Jan;10:1572; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

KCNH2-related disorder Pathogenic:1

Dec 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.1898A>G variant is predicted to result in the amino acid substitution p.Asn633Ser. This variant was reported in multiple individuals with long QT syndrome (Satler et al. 1998. PubMed ID: 9544837; Table S2, Giudicessi et al. 2012. PubMed ID: 22949429; Supplementary Table, Marschall et al. 2019. PubMed ID: 31737537). Functional studies showed that this variant results in reduced expression, abnormal trafficking, and enhanced channel inactivation (Table S4, Anderson et al. 2014. PubMed ID: 25417810; Supplementary Table, Marschall et al. 2019. PubMed ID: 31737537; Ng et al. 2020. PubMed ID: 31557540). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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:9544837;PMID:11222472;PMID:12877697;PMID:15840476;PMID:16842670;PMID:18441445;PMID:18752142;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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Pathogenic	0.84
Sift	Benign	0.055	T;D;.
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.93	P;P;.
Vest4		0.93
MutPred		0.82		.;Gain of catalytic residue at N633 (P = 0.0386);.;
MVP		0.95
MPC		1.9
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.68
gMVP		0.95

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: rs199472961; hg19: chr7-150648583;