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NM_000238.4(KCNH2):c.1754G>T (p.Trp585Leu) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 9, 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:
RCV001852296.5

Allele description [Variation Report for NM_000238.4(KCNH2):c.1754G>T (p.Trp585Leu)]

NM_000238.4(KCNH2):c.1754G>T (p.Trp585Leu)

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.1754G>T (p.Trp585Leu)
Other names:
p.W585L:TGG>TTG
HGVS:
  • NC_000007.14:g.150951639C>A
  • NG_008916.1:g.31288G>T
  • NM_000238.4:c.1754G>TMANE SELECT
  • NM_001204798.2:c.734G>T
  • NM_001406753.1:c.1466G>T
  • NM_001406755.1:c.1577G>T
  • NM_001406756.1:c.1466G>T
  • NM_001406757.1:c.1454G>T
  • NM_172056.3:c.1754G>T
  • NM_172057.3:c.734G>T
  • NP_000229.1:p.Trp585Leu
  • NP_000229.1:p.Trp585Leu
  • NP_001191727.1:p.Trp245Leu
  • NP_001393682.1:p.Trp489Leu
  • NP_001393684.1:p.Trp526Leu
  • NP_001393685.1:p.Trp489Leu
  • NP_001393686.1:p.Trp485Leu
  • NP_742053.1:p.Trp585Leu
  • NP_742053.1:p.Trp585Leu
  • NP_742054.1:p.Trp245Leu
  • NP_742054.1:p.Trp245Leu
  • LRG_288t1:c.1754G>T
  • LRG_288t2:c.1754G>T
  • LRG_288t3:c.734G>T
  • LRG_288:g.31288G>T
  • LRG_288p1:p.Trp585Leu
  • LRG_288p2:p.Trp585Leu
  • LRG_288p3:p.Trp245Leu
  • NC_000007.13:g.150648727C>A
  • NM_000238.2:c.1754G>T
  • NM_000238.3:c.1754G>T
  • NM_172056.2:c.1754G>T
  • NM_172057.2:c.734G>T
  • NR_176254.1:n.2162G>T
  • NR_176255.1:n.1035G>T
Protein change:
W245L
Links:
dbSNP: rs794728484
NCBI 1000 Genomes Browser:
rs794728484
Molecular consequence:
  • NM_000238.4:c.1754G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.734G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1466G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1577G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1466G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1454G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1754G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.734G>T - 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
SCV002304510Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Aug 9, 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

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

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, SCV002304510.3

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

Description

This sequence change replaces tryptophan with leucine at codon 585 of the KCNH2 protein (p.Trp585Leu). The tryptophan residue is highly conserved and there is a small physicochemical difference between tryptophan and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200739). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Trp585 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 25417810; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: Sep 29, 2024