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NM_000238.4(KCNH2):c.1898A>G (p.Asn633Ser) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 22, 2022
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:
RCV000617489.4

Allele description [Variation Report for NM_000238.4(KCNH2):c.1898A>G (p.Asn633Ser)]

NM_000238.4(KCNH2):c.1898A>G (p.Asn633Ser)

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.1898A>G (p.Asn633Ser)
Other names:
p.N633S:AAC>AGC
HGVS:
  • NC_000007.14:g.150951495T>C
  • NG_008916.1:g.31432A>G
  • NM_000238.4:c.1898A>GMANE SELECT
  • NM_001204798.2:c.878A>G
  • NM_001406753.1:c.1610A>G
  • NM_001406755.1:c.1721A>G
  • NM_001406756.1:c.1610A>G
  • NM_001406757.1:c.1598A>G
  • NM_172056.3:c.1898A>G
  • NM_172057.3:c.878A>G
  • NP_000229.1:p.Asn633Ser
  • NP_000229.1:p.Asn633Ser
  • NP_001191727.1:p.Asn293Ser
  • NP_001393682.1:p.Asn537Ser
  • NP_001393684.1:p.Asn574Ser
  • NP_001393685.1:p.Asn537Ser
  • NP_001393686.1:p.Asn533Ser
  • NP_742053.1:p.Asn633Ser
  • NP_742053.1:p.Asn633Ser
  • NP_742054.1:p.Asn293Ser
  • NP_742054.1:p.Asn293Ser
  • LRG_288t1:c.1898A>G
  • LRG_288t2:c.1898A>G
  • LRG_288t3:c.878A>G
  • LRG_288:g.31432A>G
  • LRG_288p1:p.Asn633Ser
  • LRG_288p2:p.Asn633Ser
  • LRG_288p3:p.Asn293Ser
  • NC_000007.13:g.150648583T>C
  • NM_000238.2:c.1898A>G
  • NM_000238.3:c.1898A>G
  • NM_172056.2:c.1898A>G
  • NM_172057.2:c.878A>G
  • NR_176254.1:n.2306A>G
  • NR_176255.1:n.1179A>G
  • Q12809:p.Asn633Ser
Protein change:
N293S
Links:
UniProtKB: Q12809#VAR_008936; dbSNP: rs199472961
NCBI 1000 Genomes Browser:
rs199472961
Molecular consequence:
  • NM_000238.4:c.1898A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.878A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1610A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1721A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1610A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1598A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1898A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.878A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000736310Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 22, 2022) 		germlineclinical testing

PubMed (22)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Structural and functional role of the extracellular s5-p linker in the HERG potassium channel.

Liu J, Zhang M, Jiang M, Tseng GN.

J Gen Physiol. 2002 Nov;120(5):723-37.

PubMed [citation]
PMID:
12407082
PMCID:
PMC2229555

Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms.

Lai LP, Su YN, Chiang FT, Juang JM, Liu YB, Ho YL, Chen WJ, Yeh SJ, Wang CC, Ko YL, Wu TJ, Ueng KC, Lei MH, Tsao HM, Chen SA, Lin TK, Wu MH, Lo HM, Huang SKS, Lin JL.

J Hum Genet. 2005;50(9):490-496. doi: 10.1007/s10038-005-0283-3. Epub 2005 Sep 10. Erratum in: J Hum Genet. 2006;51(3):267. Hsieh, Fon-Jou [added]. J Hum Genet. 2006 Mar;51(3):267. doi: 10.1007/s10038-006-0367-8.

PubMed [citation]
PMID:
16155735
See all PubMed Citations (22)

Details of each submission

From Ambry Genetics, SCV000736310.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (22)

Description

The p.N633S pathogenic mutation (also known as c.1898A>G), located in coding exon 7 of the KCNH2 gene, results from an A to G substitution at nucleotide position 1898. The asparagine at codon 633 is replaced by serine, an amino acid with highly similar properties. This alteration has been previously reported in a number of individuals with long QT syndrome (LQTS) (Satler CA et al. Hum Genet. 1998;102:265-72; Tan HL et al. Circulation. 2006;114:2096-103; Nagaoka I et al. Circ J. 2008;72:694-9; Berge KE et al. Scand J Clin Lab Invest. 2008;68:362-8; Kapa S et al. Circulation. 2009;120:1752-60; Christiansen M et al. BMC Med. Genet. 2014;15:31). In functional in vitro analyses, this variant has been suggested to affect the potassium channel current (She HR et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2006;34:523-7; Ng CA et al. Heart Rhythm. 2020 03;17(3):492-500; Perry MD et al. Cardiovasc Res. 2020 07;116(8):1434-1445) and to cause protein trafficking deficiency (Anderson CL et al. Nat Commun. 2014;5:5535; O'Hare BJ et al. Circ Genom Precis Med. 2020 10;13(5):466-475). Based on internal structural analysis, this variant is predicted to be structurally destabilizing (Liu J et al. J Gen Physiol. 2002 Nov;120(5):723-37; Butler A et a. Front Pharmacol. 2019 Jan;10:1572; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Oct 13, 2024