U.S. flag

An official website of the United States government

NM_000238.4(KCNH2):c.1418C>T (p.Thr473Ile) AND not specified

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 24, 2018
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:
RCV001000688.8

Allele description [Variation Report for NM_000238.4(KCNH2):c.1418C>T (p.Thr473Ile)]

NM_000238.4(KCNH2):c.1418C>T (p.Thr473Ile)

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.1418C>T (p.Thr473Ile)
HGVS:
  • NC_000007.14:g.150952564G>A
  • NG_008916.1:g.30363C>T
  • NM_000238.4:c.1418C>TMANE SELECT
  • NM_001204798.2:c.398C>T
  • NM_001406753.1:c.1130C>T
  • NM_001406755.1:c.1241C>T
  • NM_001406756.1:c.1130C>T
  • NM_001406757.1:c.1118C>T
  • NM_172056.3:c.1418C>T
  • NM_172057.3:c.398C>T
  • NP_000229.1:p.Thr473Ile
  • NP_000229.1:p.Thr473Ile
  • NP_001191727.1:p.Thr133Ile
  • NP_001393682.1:p.Thr377Ile
  • NP_001393684.1:p.Thr414Ile
  • NP_001393685.1:p.Thr377Ile
  • NP_001393686.1:p.Thr373Ile
  • NP_742053.1:p.Thr473Ile
  • NP_742053.1:p.Thr473Ile
  • NP_742054.1:p.Thr133Ile
  • NP_742054.1:p.Thr133Ile
  • LRG_288t1:c.1418C>T
  • LRG_288t2:c.1418C>T
  • LRG_288t3:c.398C>T
  • LRG_288:g.30363C>T
  • LRG_288p1:p.Thr473Ile
  • LRG_288p2:p.Thr473Ile
  • LRG_288p3:p.Thr133Ile
  • NC_000007.13:g.150649652G>A
  • NM_000238.3:c.1418C>T
  • NM_172056.2:c.1418C>T
  • NM_172057.2:c.398C>T
  • NR_176254.1:n.1826C>T
  • NR_176255.1:n.699C>T
Protein change:
T133I
Links:
dbSNP: rs199472905
NCBI 1000 Genomes Browser:
rs199472905
Molecular consequence:
  • NM_000238.4:c.1418C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.398C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1241C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1118C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1418C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.398C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001157725ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Likely pathogenic
(Jul 24, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157725.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The KCNH2 c.1418C>T; p.Thr473Ile variant, to our knowledge, is not reported in the medical literature or gene specific databases. Other variants at this codon (p.Thr473Pro, p.Thr473Asn), as well as an adjacent p.Thr474Ile variant, have been reported in individuals with Long QT syndrome and are considered pathogenic (Itoh 2010, Kapplinger 2009, Liu 2013, Tanaka 1997). Electrophysiological characterization of the p.Thr473Pro and p.Thr474Ile variants reveal dominant negative effects on channel activity and altered gating properties, respectively (Liu 2013, Zhou 1998), suggesting that the S2-S3 cytoplasmic loop containing Thr473 is functionally important. The c.1418C>T; p.Thr473Ile variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 473 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Itoh H et al. Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm. 2010 Oct;7(10):1411-8. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Liu L et al. A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome. Heart Rhythm. 2013 Jan;10(1):61-7. Tanaka T et al. Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. Circulation. 1997 Feb 4;95(3):565-7. Zhou Z et al. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998 Aug 14;273(33):21061-6.

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

Last Updated: Mar 4, 2023