NM_000238.4:c.340C>T

Variant names:

• chr7-150959704-G-A
• rs199472861
• NM_000238.4:c.340C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000238.4(KCNH2):​c.340C>T​(p.Pro114Ser) 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. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P114P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 9.35
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.340C>T	p.Pro114Ser	missense	Exon 3 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.52C>T	p.Pro18Ser	missense	Exon 1 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.340C>T	p.Pro114Ser	missense	Exon 3 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.340C>T	p.Pro114Ser	missense	Exon 3 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.340C>T	p.Pro114Ser	missense	Exon 3 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.40C>T	p.Pro14Ser	missense	Exon 2 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 2 Pathogenic:1

Mar 27, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the literature in at least five individuals with LQTS (PMID: 16922724, 11222472, 38489124, 32893267, 26669661, 19716085). It has also been classified as a VUS by a clinical laboratory in ClinVar; Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Pro114Leu) has been reported in one individual from a cohort of LQTS patients and classified as likely pathogenic (PMID: 32893267); Variant is located in the N-terminus PAS-associated C terminal (PAC) hotspot region (DECIPHER); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from proline to serine; This variant is heterozygous; This gene is associated with autosomal dominant disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 1 heterozygote(s), 0 homozygote(s)); Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM; PMID: 10753933, 21777565); The condition associated with this gene has incomplete penetrance (PMID: 20301308); Inheritance information for this variant is not currently available in this individual.

Long QT syndrome Uncertain:1

Dec 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 114 of the KCNH2 protein (p.Pro114Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNH2-related conditions (PMID: 11222472, 16922724, 19716085). ClinVar contains an entry for this variant (Variation ID: 67494). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810, 31557540). 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.

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:11222472;PMID:16922724;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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.88	P
Vest4		0.96
MutPred		0.92		Gain of sheet (P = 0.0477)
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.98
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs199472861; hg19: chr7-150656792;