NM_172056.2(KCNH2):c.1691T>A (p.Leu564Gln) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jul 9, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000693704.4

Allele description [Variation Report for NM_172056.2(KCNH2):c.1691T>A (p.Leu564Gln)]

NM_172056.2(KCNH2):c.1691T>A (p.Leu564Gln)

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.1691T>A (p.Leu564Gln)
HGVS:
  • NC_000007.14:g.150951702A>T
  • NG_008916.1:g.31225T>A
  • NM_000238.3:c.1691T>A
  • NM_001204798.2:c.671T>A
  • NM_172056.2:c.1691T>A
  • NM_172057.2:c.671T>A
  • NP_000229.1:p.Leu564Gln
  • NP_001191727.1:p.Leu224Gln
  • NP_742053.1:p.Leu564Gln
  • NP_742054.1:p.Leu224Gln
  • LRG_288t1:c.1691T>A
  • LRG_288t2:c.1691T>A
  • LRG_288t3:c.671T>A
  • LRG_288:g.31225T>A
  • LRG_288p1:p.Leu564Gln
  • LRG_288p2:p.Leu564Gln
  • LRG_288p3:p.Leu224Gln
  • NC_000007.13:g.150648790A>T
Protein change:
L224Q
Links:
dbSNP: rs199472924
NCBI 1000 Genomes Browser:
rs199472924
Molecular consequence:
  • NM_000238.3:c.1691T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.671T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.1691T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.2:c.671T>A - 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
SCV000821585Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 9, 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

The distinct HERG missense mutation L564P causes long QT syndrome in one French Canadian family.

St-Pierre J, Roy N, Blier L, Plante E, Cote JM, Gilbert M, Chahine M.

Can J Cardiol. 2000 Mar;16(3):307-12.

PubMed [citation]
PMID:
10744792

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, SCV000821585.4

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

Description

This sequence change replaces leucine with glutamine at codon 564 of the KCNH2 protein (p.Leu564Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with long QT syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Variants that disrupt the p.Leu564 amino acid residue in KCNH2 have been observed in affected individuals (PMID: 10744792, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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 7, 2021

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