NM_000238.4(KCNH2):c.3365dup (p.Ala1124fs) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jun 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001216294.2

Allele description [Variation Report for NM_000238.4(KCNH2):c.3365dup (p.Ala1124fs)]

NM_000238.4(KCNH2):c.3365dup (p.Ala1124fs)

Gene:
KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
7q36.1
Genomic location:
Preferred name:
NM_000238.4(KCNH2):c.3365dup (p.Ala1124fs)
HGVS:
  • NC_000007.14:g.150945484dup
  • NG_008916.1:g.37447dup
  • NM_000238.4:c.3365dupMANE SELECT
  • NM_172057.3:c.2345dup
  • NP_000229.1:p.Ala1124fs
  • NP_742054.1:p.Ala784fs
  • LRG_288t1:c.3365dup
  • LRG_288:g.37447dup
  • NC_000007.13:g.150642567_150642568insG
  • NC_000007.13:g.150642572dup
  • NM_000238.2:c.3365dupC
  • NM_000238.3:c.3365dup
Protein change:
A1124fs
Links:
Molecular consequence:
  • NM_000238.4:c.3365dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_172057.3:c.2345dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001388084Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 10, 2019)
germlineclinical testing

PubMed (2)
[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

Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation.

Sasano T, Ueda K, Orikabe M, Hirano Y, Kawano S, Yasunami M, Isobe M, Kimura A, Hiraoka M.

J Mol Cell Cardiol. 2004 Dec;37(6):1205-11.

PubMed [citation]
PMID:
15572050

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001388084.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change results in a premature translational stop signal in the KCNH2 gene (p.Ala1124Glyfs*146). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acids of the KCNH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with long QT syndrome (PMID: 15572050, Invitae). This variant is also known in the literature as 1122fs/147. This variant has been reported to affect KCNH2 protein function (PMID: 15572050). 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: Oct 24, 2021

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