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NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 13, 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:
RCV002381340.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)]

NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)

Gene:
KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.5
Genomic location:
Preferred name:
NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)
HGVS:
  • NC_000011.10:g.2583544C>T
  • NG_008935.1:g.143554C>T
  • NM_000218.3:c.1031C>TMANE SELECT
  • NM_001406836.1:c.1031C>T
  • NM_001406837.1:c.761C>T
  • NM_001406838.1:c.587C>T
  • NM_181798.2:c.650C>T
  • NP_000209.2:p.Ala344Val
  • NP_000209.2:p.Ala344Val
  • NP_001393765.1:p.Ala344Val
  • NP_001393766.1:p.Ala254Val
  • NP_001393767.1:p.Ala196Val
  • NP_861463.1:p.Ala217Val
  • NP_861463.1:p.Ala217Val
  • LRG_287t1:c.1031C>T
  • LRG_287t2:c.650C>T
  • LRG_287:g.143554C>T
  • LRG_287p1:p.Ala344Val
  • LRG_287p2:p.Ala217Val
  • NC_000011.9:g.2604774C>T
  • NM_000218.2:c.1031C>T
  • NM_181798.1:c.650C>T
  • NR_040711.2:n.924C>T
  • P51787:p.Ala344Val
Protein change:
A196V
Links:
UniProtKB: P51787#VAR_001541; dbSNP: rs199472763
NCBI 1000 Genomes Browser:
rs199472763
Molecular consequence:
  • NM_000218.3:c.1031C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.1031C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406838.1:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.650C>T - 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
SCV002699821Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 13, 2022) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes.

Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Circulation. 2004 Oct 12;110(15):2119-24. Epub 2004 Oct 4.

PubMed [citation]
PMID:
15466642

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]
PMID:
15840476
See all PubMed Citations (22)

Details of each submission

From Ambry Genetics, SCV002699821.2

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

Description

The p.A344V pathogenic mutation (also known as c.1031C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1031. The alanine at codon 344 is replaced by valine, an amino acid with similar properties. This alteration has been reported in the heterozygous state in several individuals from multiple long QT syndrome (LQTS) cohorts (Donger C et al. Circulation. 1997;96(9):2778-81; Choi G et al. Circulation. 2004;110(15):2119-24; Shimizu W et al. J. Am. Coll. Cardiol. 2004;44:117-25; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Millat G et al. Clin. Genet. 2006;70(3):214-27; Moss AJ et al. Circulation. 2007;115(19):2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Schwartz PJ et al. Eur Heart J. 2021 12;42(46):4743-4755). This variant has also been detected in the homozygous state in several individuals with severe LQTS phenotypes reminiscent of the recessive Jervell and Lange-Nielsen syndrome (JLNS) but without hearing loss (Al-Hassnan ZN et al. Heart Rhythm. 2017;epub; Bdier AT et al. Mol Gen & Gen Med. 2017:epub). Reportedly unaffected/asymptomatic heterozygous carriers of this variant have also been detected, suggesting it may result in a mild phenotype and/or exhibit reduced penetrance in the heterozygous state in some cases (Al-Hassnan ZN et al. Heart Rhythm. 2017;epub; Schwartz PJ et al. Eur Heart J. 2021 12;42(46):4743-4755). Several in vitro assays indicate this variant impacts ion channel function (Siebrands CC et al. Anesthesiology. 2006 Sep;105(3):511-20; Heijman J et al. Circ. Res. 2012 Jan;110(2):211-9; Schwartz PJ et al. Eur Heart J. 2021 12;42(46):4743-4755). Based on internal structural analysis, this variant is predicted to disturb a functionally important motif (Sun J et al. Cell. 2020 01;180(2):340-347.e9; Sun J et al. Cell. 2017 Jun;169(6):1042-1050.e9; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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: Sep 29, 2024