NM_000238.4(KCNH2):c.916G>T (p.Gly306Trp) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Dec 22, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000229643.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.916G>T (p.Gly306Trp)]

NM_000238.4(KCNH2):c.916G>T (p.Gly306Trp)

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.916G>T (p.Gly306Trp)
Other names:
p.G306W:GGG>TGG
HGVS:
  • NC_000007.14:g.150958059C>A
  • NG_008916.1:g.24868G>T
  • NM_000238.3:c.916G>T
  • NM_000238.4:c.916G>TMANE SELECT
  • NM_172056.2:c.916G>T
  • NP_000229.1:p.Gly306Trp
  • NP_000229.1:p.Gly306Trp
  • NP_742053.1:p.Gly306Trp
  • LRG_288t1:c.916G>T
  • LRG_288t2:c.916G>T
  • LRG_288:g.24868G>T
  • LRG_288p1:p.Gly306Trp
  • LRG_288p2:p.Gly306Trp
  • NC_000007.13:g.150655147C>A
  • NM_000238.2:c.916G>T
Protein change:
G306W
Links:
dbSNP: rs199472884
NCBI 1000 Genomes Browser:
rs199472884
Molecular consequence:
  • NM_000238.3:c.916G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000238.4:c.916G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.916G>T - 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
SCV000283989Invitaecriteria provided, single submitter
Likely pathogenic
(Dec 22, 2017)
germlineclinical testing

PubMed (4)
[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

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]
PMID:
15840476

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.

Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G, Oyen N, Greve G, Carlsson A, Rognum TO, Hallerud M, Kongsgård E, Amlie JP, Leren TP.

Scand J Clin Lab Invest. 2008;68(5):362-8. doi: 10.1080/00365510701765643.

PubMed [citation]
PMID:
18752142
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000283989.4

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

Description

This sequence change replaces glycine with tryptophan at codon 306 of the KCNH2 protein (p.Gly306Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. It also falls at the last nucleotide of exon 4 of the KCNH2 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with longQT syndrome (PMID: 15840476, 19038855). Nucleotide substitutions at last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Gly306Arg) is reported to be deleterious (PMID: 18752142). This indicates that the glycine residue is important for KCNH2 protein function. For these reasons, 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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