NM_000238.4(KCNH2):c.1205A>G (p.His402Arg) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 21, 2017
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:: RCV000535219.6

Allele description [Variation Report for NM_000238.4(KCNH2):c.1205A>G (p.His402Arg)]

NM_000238.4(KCNH2):c.1205A>G (p.His402Arg)

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.1205A>G (p.His402Arg)

HGVS:

NC_000007.14:g.150952777T>C
NG_008916.1:g.30150A>G
NM_000238.4:c.1205A>GMANE SELECT
NM_001204798.2:c.185A>G
NM_001406753.1:c.917A>G
NM_001406755.1:c.1028A>G
NM_001406756.1:c.917A>G
NM_001406757.1:c.905A>G
NM_172056.3:c.1205A>G
NM_172057.3:c.185A>G
NP_000229.1:p.His402Arg
NP_000229.1:p.His402Arg
NP_001191727.1:p.His62Arg
NP_001393682.1:p.His306Arg
NP_001393684.1:p.His343Arg
NP_001393685.1:p.His306Arg
NP_001393686.1:p.His302Arg
NP_742053.1:p.His402Arg
NP_742053.1:p.His402Arg
NP_742054.1:p.His62Arg
NP_742054.1:p.His62Arg
LRG_288t1:c.1205A>G
LRG_288t2:c.1205A>G
LRG_288t3:c.185A>G
LRG_288:g.30150A>G
LRG_288p1:p.His402Arg
LRG_288p2:p.His402Arg
LRG_288p3:p.His62Arg
NC_000007.13:g.150649865T>C
NM_000238.2:c.1205A>G
NM_000238.3:c.1205A>G
NM_172056.2:c.1205A>G
NM_172057.2:c.185A>G
NR_176254.1:n.1613A>G
NR_176255.1:n.486A>G
Q12809:p.His402Arg

Protein change:

H302R

Links:

UniProtKB: Q12809#VAR_074808; dbSNP: rs199473506

NCBI 1000 Genomes Browser:

rs199473506

Molecular consequence:

NM_000238.4:c.1205A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.185A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.917A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1028A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.917A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.905A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1205A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.185A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000627417	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 21, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19841300, 25348405, 19136169, 19716085, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627417

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 21, 2017)

germline

clinical testing

PubMed (5)
[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

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

UniProt: a hub for protein information.

UniProt Consortium..

Nucleic Acids Res. 2015 Jan;43(Database issue):D204-12. doi: 10.1093/nar/gku989. Epub 2014 Oct 27.

PubMed [citation]

PMID:: 25348405
PMCID:: PMC4384041

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627417.4

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

Description

This variant identified in the KCNH2 gene is located in the cytoplasmic N-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. This sequence change replaces histidine with arginine at codon 402 of the KCNH2 protein (p.His402Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (rs199473506, ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 19136169, Invitae), as well as in an individual referred for long QT syndrome genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67166). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been 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: Sep 29, 2024

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