NM_000238.4(KCNH2):c.1781G>A (p.Gly594Asp) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jul 31, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001205698.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.1781G>A (p.Gly594Asp)]

NM_000238.4(KCNH2):c.1781G>A (p.Gly594Asp)

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.1781G>A (p.Gly594Asp)
HGVS:
  • NC_000007.14:g.150951612C>T
  • NG_008916.1:g.31315G>A
  • NM_000238.3:c.1781G>A
  • NM_000238.4:c.1781G>AMANE SELECT
  • NM_001204798.2:c.761G>A
  • NM_172056.2:c.1781G>A
  • NM_172057.3:c.761G>A
  • NP_000229.1:p.Gly594Asp
  • NP_000229.1:p.Gly594Asp
  • NP_001191727.1:p.Gly254Asp
  • NP_742053.1:p.Gly594Asp
  • NP_742054.1:p.Gly254Asp
  • LRG_288t1:c.1781G>A
  • LRG_288t2:c.1781G>A
  • LRG_288:g.31315G>A
  • LRG_288p1:p.Gly594Asp
  • LRG_288p2:p.Gly594Asp
  • NC_000007.13:g.150648700C>T
  • Q12809:p.Gly594Asp
Protein change:
G254D
Links:
UniProtKB: Q12809#VAR_074838; dbSNP: rs199472931
NCBI 1000 Genomes Browser:
rs199472931
Molecular consequence:
  • NM_000238.3:c.1781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000238.4:c.1781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.1781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976; OMIM: PS192500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001376967Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 31, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

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 (7)

Details of each submission

From Invitae, SCV001376967.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces glycine with aspartic acid at codon 594 of the KCNH2 protein (p.Gly594Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals clinical features of long QT syndrome (LQTS) (PMID: 22949429, 17905336, 19716085, 23098067, 23158531). ClinVar contains an entry for this variant (Variation ID: 67271). This variant has been reported to affect KCNH2 protein function (PMID: 25417810). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Nov 27, 2021

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