NM_000238.4(KCNH2):c.1886A>C (p.Asn629Thr) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jul 31, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000475088.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.1886A>C (p.Asn629Thr)]

NM_000238.4(KCNH2):c.1886A>C (p.Asn629Thr)

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.1886A>C (p.Asn629Thr)
HGVS:
  • NC_000007.14:g.150951507T>G
  • NG_008916.1:g.31420A>C
  • NM_000238.4:c.1886A>CMANE SELECT
  • NM_001204798.2:c.866A>C
  • NM_172056.2:c.1886A>C
  • NM_172057.3:c.866A>C
  • NP_000229.1:p.Asn629Thr
  • NP_000229.1:p.Asn629Thr
  • NP_001191727.1:p.Asn289Thr
  • NP_742053.1:p.Asn629Thr
  • NP_742054.1:p.Asn289Thr
  • LRG_288t1:c.1886A>C
  • LRG_288t2:c.1886A>C
  • LRG_288:g.31420A>C
  • LRG_288p1:p.Asn629Thr
  • LRG_288p2:p.Asn629Thr
  • NC_000007.13:g.150648595T>G
  • NM_000238.2:c.1886A>C
  • NM_000238.3:c.1886A>C
Protein change:
N289T
Links:
dbSNP: rs199472957
NCBI 1000 Genomes Browser:
rs199472957
Molecular consequence:
  • NM_000238.4:c.1886A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.866A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.1886A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.866A>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
SCV000543415Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 31, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

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, SCV000543415.2

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

Description

This sequence change replaces asparagine with threonine at codon 629 of the KCNH2 protein (p.Asn629Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual affected with long QT syndrome (PMID: 17905336). ClinVar contains an entry for this variant (Variation ID: 67314). Other missense substitutions at this codon (p.Asn629Asp, p.Asn629Ser, p.Asn629Ile, p.Asn629Lys) have been determined to be pathogenic (PMID: 10973849, 16432067, 19841300, 25417810). This suggests that the asparagine residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. This variant identified in the KCNH2 gene is located in the pore region of the resulting protein (PMID: 19841300, 25348405). Experimental studies have shown that it alters the properties of the channel (PMID: 22573844). For these reasons, this variant has been classified as Likely Pathogenic.

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

Last Updated: Dec 4, 2021

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