NM_000238.4(KCNH2):c.2078T>C (p.Leu693Pro) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Oct 6, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000238.4(KCNH2):c.2078T>C (p.Leu693Pro)]

NM_000238.4(KCNH2):c.2078T>C (p.Leu693Pro)

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000238.4(KCNH2):c.2078T>C (p.Leu693Pro)
Other names:
  • NC_000007.14:g.150950988A>G
  • NG_008916.1:g.31939T>C
  • NM_000238.4:c.2078T>CMANE SELECT
  • NM_001204798.2:c.1058T>C
  • NM_172056.2:c.2078T>C
  • NM_172057.3:c.1058T>C
  • NP_000229.1:p.Leu693Pro
  • NP_000229.1:p.Leu693Pro
  • NP_001191727.1:p.Leu353Pro
  • NP_742053.1:p.Leu693Pro
  • NP_742054.1:p.Leu353Pro
  • LRG_288t1:c.2078T>C
  • LRG_288t2:c.2078T>C
  • LRG_288:g.31939T>C
  • LRG_288p1:p.Leu693Pro
  • LRG_288p2:p.Leu693Pro
  • NC_000007.13:g.150648076A>G
  • NM_000238.2:c.2078T>C
  • NM_000238.3:c.2078T>C
  • Q12809:p.Leu693Pro
Protein change:
UniProtKB: Q12809#VAR_074869; dbSNP: rs199472983
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000238.4:c.2078T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.2078T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.1058T>C - missense variant - [Sequence Ontology: SO:0001583]


Long QT syndrome (LQTS)
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)
SCV000627449Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 6, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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



UniProt: a hub for protein information.

UniProt Consortium..

Nucleic Acids Res. 2015 Jan;43(Database issue):D204-12. doi: 10.1093/nar/gku989. Epub 2014 Oct 27.

PubMed [citation]

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000627449.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)


This sequence change replaces leucine with proline at codon 693 of the KCNH2 protein (p.Leu693Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (PMID: 22949429) and was shown to segregate with long QT syndrome in an extended family (Invitae). This variant has also been observed in an individual referred for long QT syndrome genetic testing (PMID: 19716085), though it is possible that this is the same individual as referenced in PMID: 22949429. ClinVar contains an entry for this variant (Variation ID: 67359). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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

Last Updated: Dec 4, 2021

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