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NM_000238.4(KCNH2):c.1825G>A (p.Asp609Asn) AND Long QT syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 12, 2023
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:
RCV000526585.9

Allele description [Variation Report for NM_000238.4(KCNH2):c.1825G>A (p.Asp609Asn)]

NM_000238.4(KCNH2):c.1825G>A (p.Asp609Asn)

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.1825G>A (p.Asp609Asn)
HGVS:
  • NC_000007.14:g.150951568C>T
  • NG_008916.1:g.31359G>A
  • NM_000238.4:c.1825G>AMANE SELECT
  • NM_001204798.2:c.805G>A
  • NM_001406753.1:c.1537G>A
  • NM_001406755.1:c.1648G>A
  • NM_001406756.1:c.1537G>A
  • NM_001406757.1:c.1525G>A
  • NM_172056.3:c.1825G>A
  • NM_172057.3:c.805G>A
  • NP_000229.1:p.Asp609Asn
  • NP_000229.1:p.Asp609Asn
  • NP_001191727.1:p.Asp269Asn
  • NP_001393682.1:p.Asp513Asn
  • NP_001393684.1:p.Asp550Asn
  • NP_001393685.1:p.Asp513Asn
  • NP_001393686.1:p.Asp509Asn
  • NP_742053.1:p.Asp609Asn
  • NP_742053.1:p.Asp609Asn
  • NP_742054.1:p.Asp269Asn
  • NP_742054.1:p.Asp269Asn
  • LRG_288t1:c.1825G>A
  • LRG_288t2:c.1825G>A
  • LRG_288t3:c.805G>A
  • LRG_288:g.31359G>A
  • LRG_288p1:p.Asp609Asn
  • LRG_288p2:p.Asp609Asn
  • LRG_288p3:p.Asp269Asn
  • NC_000007.13:g.150648656C>T
  • NM_000238.2:c.1825G>A
  • NM_000238.3:c.1825G>A
  • NM_172056.2:c.1825G>A
  • NM_172057.2:c.805G>A
  • NR_176254.1:n.2233G>A
  • NR_176255.1:n.1106G>A
  • Q12809:p.Asp609Asn
Protein change:
D269N
Links:
UniProtKB: Q12809#VAR_009916; dbSNP: rs199472941
NCBI 1000 Genomes Browser:
rs199472941
Molecular consequence:
  • NM_000238.4:c.1825G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.805G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1537G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1648G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1537G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1525G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1825G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.805G>A - 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
SCV000627439Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 12, 2023) 		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

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT.

Circulation. 2000 Sep 5;102(10):1178-85.

PubMed [citation]
PMID:
10973849

Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations.

Lupoglazoff JM, Denjoy I, Berthet M, Neyroud N, Demay L, Richard P, Hainque B, Vaksmann G, Klug D, Leenhardt A, Maillard G, Coumel P, Guicheney P.

Circulation. 2001 Feb 27;103(8):1095-101.

PubMed [citation]
PMID:
11222472
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627439.7

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 609 of the KCNH2 protein (p.Asp609Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 11222472, 11854117, 18808722, 26669661). ClinVar contains an entry for this variant (Variation ID: 67286). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). This variant disrupts the p.Asp609 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15500450, 25417810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024