NM_000238.4(KCNH2):c.916G>C (p.Gly306Arg) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Nov 10, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000198797.4

Allele description [Variation Report for NM_000238.4(KCNH2):c.916G>C (p.Gly306Arg)]

NM_000238.4(KCNH2):c.916G>C (p.Gly306Arg)

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>C (p.Gly306Arg)
HGVS:
  • NC_000007.14:g.150958059C>G
  • NG_008916.1:g.24868G>C
  • NM_000238.3:c.916G>C
  • NM_000238.4:c.916G>CMANE SELECT
  • NM_172056.2:c.916G>C
  • NP_000229.1:p.Gly306Arg
  • NP_000229.1:p.Gly306Arg
  • NP_742053.1:p.Gly306Arg
  • LRG_288t1:c.916G>C
  • LRG_288t2:c.916G>C
  • LRG_288:g.24868G>C
  • LRG_288p1:p.Gly306Arg
  • LRG_288p2:p.Gly306Arg
  • NC_000007.13:g.150655147C>G
Protein change:
G306R
Links:
dbSNP: rs199472884
NCBI 1000 Genomes Browser:
rs199472884
Molecular consequence:
  • NM_000238.3:c.916G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000238.4:c.916G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.916G>C - 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
SCV000253680Invitaecriteria provided, single submitter
Likely pathogenic
(Nov 10, 2017)
germlineclinical testing

PubMed (3)
[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 (3)

Details of each submission

From Invitae, SCV000253680.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glycine with arginine at codon 306 of the KCNH2 protein (p.Gly306Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in two unrelated individuals with long QT syndrome (PMID: 18752142). In addition, a G>T change at this position has also been reported in an individual diagnosed with long QT syndrome (PMID: 15840476). ClinVar contains an entry for this variant (Variation ID: 67543). 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 C0"). 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. In summary, this variant is a rare missense change with uncertain impact on protein function and splicing. It is is absent from population databases, affects the last nucleotide of the exon, and has been observed in several unrelated individuals with long QT syndrome. This evidence indicates that the variant is pathogenic, but additional data is 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: Oct 25, 2021

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