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NM_000238.4(KCNH2):c.2269A>G (p.Lys757Glu) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 27, 2021
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:
RCV001963535.5

Allele description [Variation Report for NM_000238.4(KCNH2):c.2269A>G (p.Lys757Glu)]

NM_000238.4(KCNH2):c.2269A>G (p.Lys757Glu)

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.2269A>G (p.Lys757Glu)
HGVS:
  • NC_000007.14:g.150950297T>C
  • NG_008916.1:g.32630A>G
  • NM_000238.4:c.2269A>GMANE SELECT
  • NM_001204798.2:c.1249A>G
  • NM_001406753.1:c.1981A>G
  • NM_001406755.1:c.2092A>G
  • NM_001406756.1:c.1981A>G
  • NM_001406757.1:c.1969A>G
  • NM_172056.3:c.2269A>G
  • NM_172057.3:c.1249A>G
  • NP_000229.1:p.Lys757Glu
  • NP_000229.1:p.Lys757Glu
  • NP_001191727.1:p.Lys417Glu
  • NP_001393682.1:p.Lys661Glu
  • NP_001393684.1:p.Lys698Glu
  • NP_001393685.1:p.Lys661Glu
  • NP_001393686.1:p.Lys657Glu
  • NP_742053.1:p.Lys757Glu
  • NP_742053.1:p.Lys757Glu
  • NP_742054.1:p.Lys417Glu
  • NP_742054.1:p.Lys417Glu
  • LRG_288t1:c.2269A>G
  • LRG_288t2:c.2269A>G
  • LRG_288t3:c.1249A>G
  • LRG_288:g.32630A>G
  • LRG_288p1:p.Lys757Glu
  • LRG_288p2:p.Lys757Glu
  • LRG_288p3:p.Lys417Glu
  • NC_000007.13:g.150647385T>C
  • NM_000238.3:c.2269A>G
  • NM_172056.2:c.2269A>G
  • NM_172057.2:c.1249A>G
  • NR_176254.1:n.2677A>G
  • NR_176255.1:n.1550A>G
Protein change:
K417E
Links:
dbSNP: rs2116949798
NCBI 1000 Genomes Browser:
rs2116949798
Molecular consequence:
  • NM_000238.4:c.2269A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.1249A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1981A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.2092A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1981A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1969A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.2269A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.1249A>G - 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
SCV002257224Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 27, 2021) 		germlineclinical testing

PubMed (3)
[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

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]
PMID:
22949429
PMCID:
PMC3705705

Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome.

Anderson CL, Kuzmicki CE, Childs RR, Hintz CJ, Delisle BP, January CT.

Nat Commun. 2014 Nov 24;5:5535. doi: 10.1038/ncomms6535.

PubMed [citation]
PMID:
25417810
PMCID:
PMC4243539
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002257224.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Lys757 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 22949429, 25417810; Invitae), which suggests that this may be a clinically significant amino acid residue. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 757 of the KCNH2 protein (p.Lys757Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid.

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

Last Updated: Sep 29, 2024