NM_000238.4(KCNH2):c.2653C>T (p.Arg885Cys) AND Congenital long QT syndrome

Germline classification:: Benign (2 submissions)
Last evaluated:: Aug 8, 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:: RCV000058147.12

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:: Congenital long QT syndrome (RWS)
Synonyms:: Familial long QT syndrome; Romano-Ward syndrome; Ventricular fibrillation with prolonged QT interval
Identifiers:: MONDO: MONDO:0019171; MedGen: C1141890; Orphanet: 768; OMIM: PS192500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000089667	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (6) [See all records that cite these PMIDs] 16244680, 17210839, 18752142, 19716085, 22378279, 22581653
SCV004175713	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Aug 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18752142, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000089667

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

no classification provided

not provided

germline

literature only

PubMed (6)
[See all records that cite these PMIDs]

SCV004175713

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Aug 8, 2023)

germline

clinical testing

PubMed (3)
[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	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

[DNA-based diagnostics of long QT syndrome].

Berge KE, Haugaa KH, Anfinsen OG, Früh A, Hallerud M, Jonsrud C, Øyen N, Gjesdal K, Amlie JP, Leren TP.

Tidsskr Nor Laegeforen. 2005 Oct 20;125(20):2783-6. Norwegian.

PubMed [citation]

PMID:: 16244680

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

See all PubMed Citations (8)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089667.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

Description

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16244680;PMID:17210839;PMID:18752142;PMID:19716085;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

#	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

From Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations, SCV004175713.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Heterozygous variant NM_000238:c.2653C>T (p.Arg885Cys) in the KCNH2 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. An additional variant NM_003098:c.787G>T (p.Ala263Ser) in the SNTA1 gene was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0002065 (Date of access 08-08-2023). Clinvar contains entry for this variant (Variation ID: 67422). This variant has been reported in over a dozen studies in patients with variable phenotypes. Experimental data showed the variant exhibited biophysical properties indistinguishable from WT-HERG (PMID: 18752142). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Benign with following criteria selected: BS1, BS3, PM1, PP2, PP3.

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

Last Updated: Nov 3, 2024

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