chr7-150974803-G-T

Variant names:

• chr7-150974803-G-T
• rs199473421
• NM_000238.4:c.215C>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.215C>A​(p.Pro72Gln) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.88
• Publications: 9 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain 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 chr7-150974804-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200564.
• 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, 0.967
• PP5: Variant 7-150974803-G-T is Pathogenic according to our data. Variant chr7-150974803-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.215C>A	p.Pro72Gln	missense	Exon 2 of 15	NP_000229.1
	KCNH2	NM_172056.3		c.215C>A	p.Pro72Gln	missense	Exon 2 of 9	NP_742053.1
	KCNH2	NM_001406755.1		c.38C>A	p.Pro13Gln	missense	Exon 2 of 9	NP_001393684.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.215C>A	p.Pro72Gln	missense	Exon 2 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.215C>A	p.Pro72Gln	missense	Exon 2 of 15	ENSP00000519013.1
	KCNH2	ENST00000532957.5	TSL:2	n.438C>A		non_coding_transcript_exon	Exon 2 of 9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 12, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Dec 15, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM2, PM5, PS4

Cardiovascular phenotype Pathogenic:2

Feb 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.215C>A affects a conserved nucleotide, resulting in amino acid change from Pro to Gln. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index), and functional studies indicate P72Q to have deficient trafficking (Anderson_2014). This variant was not found in 70930 control chromosomes, but has been reported in multiple LQT2 pts. In addition, multiple clinical laboratories classified this variant as pathogenic. Taken together, this variant was classified as a disease variant/pathogenic.

Mar 31, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P72Q pathogenic mutation (also known as c.215C>A), located in coding exon 2 of the KCNH2 gene, results from a C to A substitution at nucleotide position 215. The proline at codon 72 is replaced by glutamine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with long QT syndrome and segregated with disease in at least one family (Moss AJ et al. Circulation. 2002;105:794-9; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Itoh H et al. Eur. J. Hum. Genet. 2016;24:1160-6; external communication; Ambry internal data). One study reported this alteration to result in abnormal protein trafficking (Anderson CL et al. Nat Commun. 2014;5:5535). Other variant(s) at the same codon, p.P72L (c.215C>T), have been identified in individual(s) with features consistent with long QT syndrome (Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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.

Long QT syndrome 2 Pathogenic:1

Dec 13, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.215C>A gene variant results in an amino acid change from a proline to a glutamine at position 72 in the encoded protein (p.Pro72Gln). This variant is absent from general population databases (gnomAD). This variant has been previously reported in individuals with long QT syndrome (PMID: 11854117, 20486126, 21440677, 10973849, 19716085). Experimental studies suggest this variant results in a deleterious effect on protein trafficking (PMID: 25417810). In addition, other variants at the same codon (p.Pro72Arg and p.Pro72Leu) have been previously reported in individuals with long QT syndrome (PMID: 19716085, 25417810, 23158531). Therefore, this c.215C>A variant in the KCNH2 gene is classified as likely pathogenic.

Long QT syndrome Pathogenic:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 72 of the KCNH2 protein (p.Pro72Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 19716085, 21440677; internal data). ClinVar contains an entry for this variant (Variation ID: 67368). 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). This variant disrupts the p.Pro72 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 20960620, 26496715), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified 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:10973849;PMID:11854117;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	Uncertain	0.43
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.79
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.82	P
Vest4		0.59
MutPred		0.90		Gain of MoRF binding (P = 0.0568)
MVP		0.95
MPC		1.5
ClinPred		0.87	D
GERP RS		3.6
Varity_R		0.61
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs199473421; hg19: chr7-150671891;