NM_172056.2(KCNH2):c.1805T>C (p.Leu602Pro) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jun 8, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000464070.6

Allele description [Variation Report for NM_172056.2(KCNH2):c.1805T>C (p.Leu602Pro)]

NM_172056.2(KCNH2):c.1805T>C (p.Leu602Pro)

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_172056.2(KCNH2):c.1805T>C (p.Leu602Pro)
HGVS:
  • NC_000007.14:g.150951588A>G
  • NG_008916.1:g.31339T>C
  • NM_000238.3:c.1805T>C
  • NM_001204798.2:c.785T>C
  • NM_172056.2:c.1805T>C
  • NM_172057.2:c.785T>C
  • NP_000229.1:p.Leu602Pro
  • NP_001191727.1:p.Leu262Pro
  • NP_742053.1:p.Leu602Pro
  • NP_742054.1:p.Leu262Pro
  • LRG_288t1:c.1805T>C
  • LRG_288t2:c.1805T>C
  • LRG_288t3:c.785T>C
  • LRG_288:g.31339T>C
  • LRG_288p1:p.Leu602Pro
  • LRG_288p2:p.Leu602Pro
  • LRG_288p3:p.Leu262Pro
  • NC_000007.13:g.150648676A>G
  • NM_000238.2:c.1805T>C
Protein change:
L262P
Links:
dbSNP: rs876661348
NCBI 1000 Genomes Browser:
rs876661348
Molecular consequence:
  • NM_000238.3:c.1805T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.1805T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.2:c.785T>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
SCV000543459Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 8, 2020)
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

High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance.

Steffensen AB, Refaat MM, David JP, Mujezinovic A, Calloe K, Wojciak J, Nussbaum RL, Scheinman MM, Schmitt N.

Sci Rep. 2015 Jun 12;5:10009. doi: 10.1038/srep10009.

PubMed [citation]
PMID:
26066609
PMCID:
PMC4464365

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, SCV000543459.6

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

Description

This sequence change replaces leucine with proline at codon 602 of the KCNH2 protein (p.Leu602Pro). The leucine residue is weakly 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 observed in individuals affected with long QT syndrome (PMID: 26066609, Invitae). ClinVar contains an entry for this variant (Variation ID: 234996). 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 tolerated, 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.

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

Last Updated: Sep 23, 2021

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