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NM_000238.4(KCNH2):c.1826A>C (p.Asp609Ala) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 27, 2017
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000534743.8

Allele description [Variation Report for NM_000238.4(KCNH2):c.1826A>C (p.Asp609Ala)]

NM_000238.4(KCNH2):c.1826A>C (p.Asp609Ala)

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.1826A>C (p.Asp609Ala)
HGVS:
  • NC_000007.14:g.150951567T>G
  • NG_008916.1:g.31360A>C
  • NM_000238.4:c.1826A>CMANE SELECT
  • NM_001204798.2:c.806A>C
  • NM_001406753.1:c.1538A>C
  • NM_001406755.1:c.1649A>C
  • NM_001406756.1:c.1538A>C
  • NM_001406757.1:c.1526A>C
  • NM_172056.3:c.1826A>C
  • NM_172057.3:c.806A>C
  • NP_000229.1:p.Asp609Ala
  • NP_000229.1:p.Asp609Ala
  • NP_001191727.1:p.Asp269Ala
  • NP_001393682.1:p.Asp513Ala
  • NP_001393684.1:p.Asp550Ala
  • NP_001393685.1:p.Asp513Ala
  • NP_001393686.1:p.Asp509Ala
  • NP_742053.1:p.Asp609Ala
  • NP_742053.1:p.Asp609Ala
  • NP_742054.1:p.Asp269Ala
  • NP_742054.1:p.Asp269Ala
  • LRG_288t1:c.1826A>C
  • LRG_288t2:c.1826A>C
  • LRG_288t3:c.806A>C
  • LRG_288:g.31360A>C
  • LRG_288p1:p.Asp609Ala
  • LRG_288p2:p.Asp609Ala
  • LRG_288p3:p.Asp269Ala
  • NC_000007.13:g.150648655T>G
  • NM_000238.3:c.1826A>C
  • NM_172056.2:c.1826A>C
  • NM_172057.2:c.806A>C
  • NR_176254.1:n.2234A>C
  • NR_176255.1:n.1107A>C
Protein change:
D269A
Links:
dbSNP: rs199472940
NCBI 1000 Genomes Browser:
rs199472940
Molecular consequence:
  • NM_000238.4:c.1826A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.806A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1538A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1649A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1538A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1526A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1826A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.806A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000627440Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Feb 27, 2017) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Extracellular K+ is a prerequisite for the function and plasma membrane stability of HERG channels.

Massaeli H, Guo J, Xu J, Zhang S.

Circ Res. 2010 Apr 2;106(6):1072-82. doi: 10.1161/CIRCRESAHA.109.215970. Epub 2010 Feb 4.

PubMed [citation]
PMID:
20133899

Intracellular potassium stabilizes human ether-à-go-go-related gene channels for export from endoplasmic reticulum.

Wang L, Dennis AT, Trieu P, Charron F, Ethier N, Hebert TE, Wan X, Ficker E.

Mol Pharmacol. 2009 Apr;75(4):927-37. doi: 10.1124/mol.108.053793. Epub 2009 Jan 12.

PubMed [citation]
PMID:
19139152
PMCID:
PMC2684933
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627440.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNH2-related disease. Experimental studies do not agree on the effect of this variant on channel function (PMID: 20133899, 19139152, 24725272). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Asp609Gly) has been determined to be pathogenic (PMID: 15500450, 25417810). This suggests that the aspartic acid residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. This sequence change replaces aspartic acid with alanine at codon 609 of the KCNH2 protein (p.Asp609Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant identified in the KCNH2 gene is located in the transmembrane spanning S5/pore region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology.

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

Last Updated: Sep 29, 2024