NM_000238.4(KCNH2):c.1582C>T (p.Arg528Trp) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 6, 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:: RCV002399763.9

Allele description [Variation Report for NM_000238.4(KCNH2):c.1582C>T (p.Arg528Trp)]

NM_000238.4(KCNH2):c.1582C>T (p.Arg528Trp)

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.1582C>T (p.Arg528Trp)

HGVS:

NC_000007.14:g.150951811G>A
NG_008916.1:g.31116C>T
NM_000238.4:c.1582C>TMANE SELECT
NM_001204798.2:c.562C>T
NM_001406753.1:c.1294C>T
NM_001406755.1:c.1405C>T
NM_001406756.1:c.1294C>T
NM_001406757.1:c.1282C>T
NM_172056.3:c.1582C>T
NM_172057.3:c.562C>T
NP_000229.1:p.Arg528Trp
NP_000229.1:p.Arg528Trp
NP_001191727.1:p.Arg188Trp
NP_001393682.1:p.Arg432Trp
NP_001393684.1:p.Arg469Trp
NP_001393685.1:p.Arg432Trp
NP_001393686.1:p.Arg428Trp
NP_742053.1:p.Arg528Trp
NP_742053.1:p.Arg528Trp
NP_742054.1:p.Arg188Trp
NP_742054.1:p.Arg188Trp
LRG_288t1:c.1582C>T
LRG_288t2:c.1582C>T
LRG_288t3:c.562C>T
LRG_288:g.31116C>T
LRG_288p1:p.Arg528Trp
LRG_288p2:p.Arg528Trp
LRG_288p3:p.Arg188Trp
NC_000007.13:g.150648899G>A
NM_000238.2:c.1582C>T
NM_000238.3:c.1582C>T
NM_172056.2:c.1582C>T
NM_172057.2:c.562C>T
NR_176254.1:n.1990C>T
NR_176255.1:n.863C>T

Protein change:

R188W

Links:

dbSNP: rs864622403

NCBI 1000 Genomes Browser:

rs864622403

Molecular consequence:

NM_000238.4:c.1582C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.562C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1294C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1405C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1294C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1282C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1582C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.562C>T - 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
SCV002705619	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 6, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16166152, 23631430 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002705619

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 6, 2018)

germline

clinical testing

PubMed (2)
[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

Tryptophan scanning mutagenesis of the HERG K+ channel: the S4 domain is loosely packed and likely to be lipid exposed.

Subbiah RN, Kondo M, Campbell TJ, Vandenberg JI.

J Physiol. 2005 Dec 1;569(Pt 2):367-79. Epub 2005 Sep 15.

PubMed [citation]

PMID:: 16166152
PMCID:: PMC1464230

Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.

Lieve KV, Williams L, Daly A, Richard G, Bale S, Macaya D, Chung WK.

Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. doi: 10.1089/gtmb.2012.0118. Epub 2013 Apr 30.

PubMed [citation]

PMID:: 23631430

Details of each submission

From Ambry Genetics, SCV002705619.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.R528W variant (also known as c.1582C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1582. The arginine at codon 528 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been previously reported in a cohort of individuals referred for long QT syndrome genetic testing, but clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). In vitro functional studies in Xenopus oocytes has suggested that this variant may impact protein function; however, the physiological relevance of that impact is unclear (Subbiah RN et al. J. Physiol. (Lond.). 2005;569:367-79). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 1, 2024

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