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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 9, 2023
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:: RCV001841714.11

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:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Homologene neighbors for GEO Profiles (Select 82318861) (0)
GEO Profiles
BATF2 basic leucine zipper ATF-like transcription factor 2 [Homo sapiens]
BATF2 basic leucine zipper ATF-like transcription factor 2 [Homo sapiens]
Gene ID:116071

Gene
OMIM Links for Protein (Select 663854603) (12)
OMIM

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001360101	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15840476, 22653970, 26743238, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001360101

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 9, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]

PMID:: 15840476

Long QT2 mutation on the Kv11.1 ion channel inhibits current activity by ablating a protein kinase Cα consensus site.

Donovan AJ, Lansu K, Williams JG, Denning MF, Gentile S.

Mol Pharmacol. 2012 Sep;82(3):428-37. doi: 10.1124/mol.112.077966. Epub 2012 May 31. Erratum in: Mol Pharmacol. 2019 Sep;96(3):377. doi: 10.1124/mol.119.077966err.

PubMed [citation]

PMID:: 22653970
PMCID:: PMC6673708

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001360101.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with histidine at codon 887 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant may inhibit PKC-dependent phosphorylation and ultimately inhibit cell surface expression and function of the potassium channel (PMID: 22653970). This variant has been reported in an individual affected with arrhythmia (PMID 26743238) and in an individual referred for long QT genetic testing (PMID: 15840476). This variant has been identified in 2/248800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Nov 3, 2024

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