NM_000238.4(KCNH2):c.2653C>T (p.Arg885Cys) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 20, 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:: RCV001841713.11

Allele description [Variation Report for NM_000238.4(KCNH2):c.2653C>T (p.Arg885Cys)]

NM_000238.4(KCNH2):c.2653C>T (p.Arg885Cys)

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.2653C>T (p.Arg885Cys)

HGVS:

NC_000007.14:g.150948483G>A
NG_008916.1:g.34444C>T
NM_000238.4:c.2653C>TMANE SELECT
NM_172057.3:c.1633C>T
NP_000229.1:p.Arg885Cys
NP_000229.1:p.Arg885Cys
NP_742054.1:p.Arg545Cys
LRG_288t1:c.2653C>T
LRG_288:g.34444C>T
LRG_288p1:p.Arg885Cys
NC_000007.13:g.150645571G>A
NM_000238.3:c.2653C>T
Q12809:p.Arg885Cys

Protein change:

R545C

Links:

UniProtKB: Q12809#VAR_074886; dbSNP: rs143512106

NCBI 1000 Genomes Browser:

rs143512106

Molecular consequence:

NM_000238.4:c.2653C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1633C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001360100	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 20, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17210839, 18222468, 18752142, 19716085, 27920829, 30369311, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001360100

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 20, 2023)

germline

clinical testing

PubMed (7)
[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

Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.

Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George AL Jr, Schwartz PJ.

Circulation. 2007 Jan 23;115(3):361-7. Epub 2007 Jan 8.

PubMed [citation]

PMID:: 17210839

Cardiac potassium channel dysfunction in sudden infant death syndrome.

Rhodes TE, Abraham RL, Welch RC, Vanoye CG, Crotti L, Arnestad M, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Rognum T, Roden DM, Schwartz PJ, George AL Jr.

J Mol Cell Cardiol. 2008 Mar;44(3):571-81. doi: 10.1016/j.yjmcc.2007.11.015. Epub 2007 Dec 7.

PubMed [citation]

PMID:: 18222468
PMCID:: PMC2386856

See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001360100.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces arginine with cysteine at codon 885 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). A functional study has shown that this variant does not change the biophysical properties of the protein (PMID: 18222468). This variant has been reported in several individuals affected with or suspected of having long QT syndrome (PMID: 18752142, 19716085, 27920829, 30369311), and in another individual affected with sudden infant death syndrome (PMID: 17210839). One of these individuals also carried a pathogenic splicing variant in the KCNH2 gene that could explain the observed phenotype (PMID: 27920829). This variant has also been identified in 58/280856 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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