NM_000238.4(KCNH2):c.2660G>A (p.Arg887His) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 12, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002426617.9

Allele description [Variation Report for NM_000238.4(KCNH2):c.2660G>A (p.Arg887His)]

NM_000238.4(KCNH2):c.2660G>A (p.Arg887His)

Gene:

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.2660G>A (p.Arg887His)

HGVS:

NC_000007.14:g.150948476C>T
NG_008916.1:g.34451G>A
NM_000238.4:c.2660G>AMANE SELECT
NM_172057.3:c.1640G>A
NP_000229.1:p.Arg887His
NP_000229.1:p.Arg887His
NP_742054.1:p.Arg547His
LRG_288t1:c.2660G>A
LRG_288:g.34451G>A
LRG_288p1:p.Arg887His
NC_000007.13:g.150645564C>T
NM_000238.2:c.2660G>A
NM_000238.3:c.2660G>A
Q12809:p.Arg887His

Protein change:

R547H

Links:

UniProtKB: Q12809#VAR_068281; dbSNP: rs199473432

NCBI 1000 Genomes Browser:

rs199473432

Molecular consequence:

NM_000238.4:c.2660G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1640G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002744117	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 12, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17161064, 22378279, 22653970, 22927196, 26743238 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002744117

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 12, 2018)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes.

Mank-Seymour AR, Richmond JL, Wood LS, Reynolds JM, Fan YT, Warnes GR, Milos PM, Thompson JF.

Am Heart J. 2006 Dec;152(6):1116-22.

PubMed [citation]

PMID:: 17161064

High prevalence of genetic variants previously associated with LQT syndrome in new exome data.

Refsgaard L, Holst AG, Sadjadieh G, Haunsø S, Nielsen JB, Olesen MS.

Eur J Hum Genet. 2012 Aug;20(8):905-8. doi: 10.1038/ejhg.2012.23. Epub 2012 Feb 29.

PubMed [citation]

PMID:: 22378279
PMCID:: PMC3400735

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002744117.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.R887H variant (also known as c.2660G>A), located in coding exon 11 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2660. The arginine at codon 887 is replaced by histidine, an amino acid with highly similar properties. This variant was previously described in a long QT syndrome genetic testing cohort and in a primary electrical syndrome cohort (Tester et al. Heart Rhythm. 2005;2(5):507-17; Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440). In functional in vitro analyses, this variant adversely affected the potassium ion channel by inhibiting surface expression and current density (Donovan AJ et al. Mol Pharmacol. 2012;82(3):428-37). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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