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NM_000238.4(KCNH2):c.1780G>C (p.Gly594Arg) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 27, 2020
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:
RCV001327509.8

Allele description [Variation Report for NM_000238.4(KCNH2):c.1780G>C (p.Gly594Arg)]

NM_000238.4(KCNH2):c.1780G>C (p.Gly594Arg)

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.1780G>C (p.Gly594Arg)
HGVS:
  • NC_000007.14:g.150951613C>G
  • NG_008916.1:g.31314G>C
  • NM_000238.4:c.1780G>CMANE SELECT
  • NM_001204798.2:c.760G>C
  • NM_001406753.1:c.1492G>C
  • NM_001406755.1:c.1603G>C
  • NM_001406756.1:c.1492G>C
  • NM_001406757.1:c.1480G>C
  • NM_172056.3:c.1780G>C
  • NM_172057.3:c.760G>C
  • NP_000229.1:p.Gly594Arg
  • NP_000229.1:p.Gly594Arg
  • NP_001191727.1:p.Gly254Arg
  • NP_001393682.1:p.Gly498Arg
  • NP_001393684.1:p.Gly535Arg
  • NP_001393685.1:p.Gly498Arg
  • NP_001393686.1:p.Gly494Arg
  • NP_742053.1:p.Gly594Arg
  • NP_742053.1:p.Gly594Arg
  • NP_742054.1:p.Gly254Arg
  • NP_742054.1:p.Gly254Arg
  • LRG_288t1:c.1780G>C
  • LRG_288t2:c.1780G>C
  • LRG_288t3:c.760G>C
  • LRG_288:g.31314G>C
  • LRG_288p1:p.Gly594Arg
  • LRG_288p2:p.Gly594Arg
  • LRG_288p3:p.Gly254Arg
  • NC_000007.13:g.150648701C>G
  • NM_000238.3:c.1780G>C
  • NM_172056.2:c.1780G>C
  • NM_172057.2:c.760G>C
  • NR_176254.1:n.2188G>C
  • NR_176255.1:n.1061G>C
Protein change:
G254R
Links:
dbSNP: rs1801167694
NCBI 1000 Genomes Browser:
rs1801167694
Molecular consequence:
  • NM_000238.4:c.1780G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.760G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1492G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1603G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1492G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1480G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1780G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.760G>C - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001518588Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 27, 2020) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]
PMID:
22949429
PMCID:
PMC3705705

Long QT and Brugada syndrome gene mutations in New Zealand.

Chung SK, MacCormick JM, McCulley CH, Crawford J, Eddy CA, Mitchell EA, Shelling AN, French JK, Skinner JR, Rees MI.

Heart Rhythm. 2007 Oct;4(10):1306-14. Epub 2007 Jul 14.

PubMed [citation]
PMID:
17905336
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001518588.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This variant has not been reported in the literature in individuals with KCNH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 594 of the KCNH2 protein (p.Gly594Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gly594 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22949429, 17905336, 25417810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024