7-150950311-C-T

Variant names:

• chr7-150950311-C-T
• rs121912512
• NM_000238.4:c.2255G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2255G>A​(p.Arg752Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R752W) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 30)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 7.90
• Publications: 14 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 17 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, 14 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 chr7-150950312-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 67379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.918
• PP5: Variant 7-150950311-C-T is Pathogenic according to our data. Variant chr7-150950311-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14435.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.2255G>A	p.Arg752Gln	missense	Exon 9 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.1967G>A	p.Arg656Gln	missense	Exon 7 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.2255G>A	p.Arg752Gln	missense	Exon 9 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.2255G>A	p.Arg752Gln	missense	Exon 9 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1235G>A	p.Arg412Gln	missense	Exon 5 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.1553G>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250528 AF XY: 0.00

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 38

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000484 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Pathogenic:2

Aug 31, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.2255G>A (p.Arg752Gln) variant has been reported in two individuals affected with Long QT syndrome, one heterozygote (Choi SH et al., PMID: 34319147) and one homozygote (Johnson WH et al., PMID: 12621127). Johnson and colleagues make note that three family members to the homozygous patient were heterozygous for the p.Arg752Gln variant and were asymptomatic (Johnson WH et al., PMID: 12621127). The variant is only observed on 2 alleles out of 281,892 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Functional studies show that this variant leads to significantly decreased channel function and disrupts protein trafficking (Anderson CL et al., PMID: 25417810; Johnson WH et al., PMID: 12621127). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNH2 function. Another variant in the same codon, c.2254C>T (p.Arg752Trp), has been reported in affected individuals with Long QT and is considered pathogenic (Ficker E et al., PMID: 11009462; Itoh H et al., PMID: 26669661; Nagaoka I et al., PMID: 18441445; Splawski I et al., PMID: 10973849; Stattin EL et al., PMID: 23098067, ClinVar Variation ID: 67379). This variant has been reported in the ClinVar database as a pathogenic variant, a likely pathogenic variant, and a variant of uncertain significance by one submitter each in association for Long QT syndrome. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Long QT syndrome Pathogenic:1 Uncertain:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 752 of the KCNH2 protein (p.Arg752Gln). This variant is present in population databases (rs121912512, gnomAD 0.008%). This missense change has been observed in individuals with long QT interval (PMID: 12621127, 34319147; Invitae). ClinVar contains an entry for this variant (Variation ID: 14435). 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: 12621127, 25417810). This variant disrupts the p.Arg752 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 11009462, 18441445). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

not provided Pathogenic:1

Jul 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a homozygous variant in a patient with Long QT syndrome diagnosed in utero; however, heterozygous family members had normal QT intervals (PMID: 12621127); Published functional studies demonstrate a damaging effect as this variant leads to significantly decreased channel function and causes a protein trafficking defect (PMID: 12621127, 25417810); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25417810, 25637381, 37324772, 34309407, 12621127, 34570182, 34319147)

Cardiovascular phenotype Pathogenic:1

Jan 21, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2255G>A (p.R752Q) alteration is located in exon 9 (coding exon 9) of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 2255, causing the arginine (R) at amino acid position 752 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/281892) total alleles studied. The highest observed frequency was 0.008% (2/24810) of African alleles. This variant has been reported in individuals with features consistent with long QT syndrome (Johnson, 2003; Choi, 2021; external communication). Another variant at the same codon, p.R752W (c.2254C>T), has been identified in individuals with features consistent with long QT syndrome (Splawski, 2000; Ficker, 2000). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest this variant may impact protein function; however, additional evidence is needed to confirm these findings (Johnson, 2003; Anderson, 2014; Li, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Cardiac arrhythmia Pathogenic:1

Nov 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 752 of the KCNH2 protein. This variant is found within the highly conserved cyclic nucleotide binding region (a.a. 742-842). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes deficient maturation and trafficking of KCNH2 protein to the cell surface (PMID: 25417810), and results in reduced channel currents (PMID: 12621127). This variant has been reported in homozygous status in an individual affected with severe neonatal long QT syndrome while three heterozygous carriers in the family were reported to be asymptomatic (PMID: 12621127). This variant has also been reported in another two unrelated heterozygous individuals affected with long QT syndrome (PMID: 34319147, ClinVar: SCV000253679.4). This variant has been identified in 2/281892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg752Trp, is known to be disease-causing (ClinVar variation ID: 67379), indicating that arginine at this position is important for KCNH2 protein function. Based on the available evidence, this variant is classified as Likely 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:12621127). 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	0.98
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.59
gMVP		0.84
Mutation Taster		=2/98	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: rs121912512; hg19: chr7-150647399; COSMIC: COSV51137157;