• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
KCNH2 (HGNC:6251) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
potassium voltage-gated channel subfamily H member 2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
LQT2
Alias symbols
Kv11.1, HERG, erg1
%HI
8.87(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.27(Read more about gnomAD LOEUF score)
Cytoband
7q36.1
Genomic Coordinates
GRCh37/hg19: chr7:150642049-150675409 NCBI Ensembl UCSC
GRCh38/hg38: chr7:150944961-150978321 NCBI Ensembl UCSC
MANE Select Transcript
NM_000238.4 ENST00000262186.10 (Read more about MANE Select)
Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr) (PubMed:18559421, PubMed:26363003, PubMed:27916661). {ECO:0000269|PubMed:18559421, ECO:0000269|PubMed:26363003, ECO:0000269|PubMed:27916661}. [Isoform A-USO]: Has no channel activity by itself, but modulates channel characteristics by forming heterote... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-29433
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
02/26/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 18774102
    Eddy et al (2008) describe a proband diagnosed with Long QT syndrome (LQTS) at 22 years of age. She had experienced syncope and seizures from age 9, and her sister was diagnosed with epilepsy and died suddenly at age 36. The proband was found to carry a deletion of exons 6-14 of KCNH2. Her affected father declined testing. A second proband was diagnosed with LQTS at 12 years of age after the sudden death of his mother at 32 years of age. The child was asymptomatic. Several maternal family members were also affected and died suddenly. The proband was found to have an intragenic duplication of exons 9-14. The authors propose a haploinsufficiency effect for the deletion, and possibly a dominant-negative effect for the duplication, although functional studies have not been performed.
  • PUBMED: 24530480
    Gong et al (2014) used a minigene in vitro model system to investigate the mechanism of two truncating mutations observed in LQTS patients, W1001X and R1014X. The studies demonstrated reduced mRNA levels, suggestive of a haploinsufficient effect.
HI Evidence Comments:
There is a significant amount of evidence suggesting that loss of KCNH2 results in Long QT syndrome (LQTS). In addition to the evidence above, Itoh et al 2016 (PMID: 26669661) report 280 KCNH2 variants in families with LQTS; 95/280 were nonsense, frameshift or splice site variants (>100 families with multiple affected individuals) (Supplementary Table 2). Stattin et al 2012 (PMID: 23098067 ) reports 3 additional affected probands with truncating variants. HGMD also catalogs a number of putative loss of function variants, including: 70 disease causing nonsense variants,17 disease causing splice site variants (+/-2), 6 large deletions (multiple exons), and 141 disease causing frame shift variants. Of note, large deletions involving KCNH2 in addition to other genes have also been observed in individuals diagnosed with Long QT syndrome. Barc et al (2011) (PMID: 21185499) studied 93 patients with LQTS who had experienced symptoms such as syncope, arrhythmia, and cardiac arrest. Two probands were found with deletion in KCNH2. The proband of Family 1 was 23 years old with a 650 kb deletion of exons 4-14 (+19 other genes centromeric to KCNH2). Six other carrier family members had LQTS but were asymptomatic. The proband of Family 2 was 28 years old with a 145 kb deletion of the entire KCNH2 and ABP1 genes. The deletion was also found in her affected mother and "healthy" brother.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000007.13) (NC_000007.14)