NM_000218.3(KCNQ1):c.944A>G (p.Tyr315Cys) AND Cardiovascular phenotype

Clinical significance:Pathogenic (Last evaluated: Mar 12, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000619103.1

Allele description [Variation Report for NM_000218.3(KCNQ1):c.944A>G (p.Tyr315Cys)]

NM_000218.3(KCNQ1):c.944A>G (p.Tyr315Cys)

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.944A>G (p.Tyr315Cys)
Other names:
p.Y315C:TAT>TGT
HGVS:
  • NC_000011.10:g.2583457A>G
  • NG_008935.1:g.143467A>G
  • NM_000218.3:c.944A>GMANE SELECT
  • NM_181798.1:c.563A>G
  • NP_000209.2:p.Tyr315Cys
  • NP_000209.2:p.Tyr315Cys
  • NP_861463.1:p.Tyr188Cys
  • LRG_287t1:c.944A>G
  • LRG_287t2:c.563A>G
  • LRG_287:g.143467A>G
  • LRG_287p1:p.Tyr315Cys
  • LRG_287p2:p.Tyr188Cys
  • NC_000011.9:g.2604687A>G
  • NM_000218.2:c.944A>G
  • P51787:p.Tyr315Cys
Protein change:
Y188C
Links:
UniProtKB: P51787#VAR_008946; dbSNP: rs74462309
NCBI 1000 Genomes Browser:
rs74462309
Molecular consequence:
  • NM_000218.3:c.944A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.1:c.563A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000737748Ambry Geneticscriteria provided, single submitter
Pathogenic
(Mar 12, 2019)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias.

Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A, Acquaro G, Priori SG.

J Cardiovasc Electrophysiol. 2000 Jun;11(6):691-6.

PubMed [citation]
PMID:
10868744

Mechanisms of I(Ks) suppression in LQT1 mutants.

Bianchi L, Priori SG, Napolitano C, Surewicz KA, Dennis AT, Memmi M, Schwartz PJ, Brown AM.

Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3003-11.

PubMed [citation]
PMID:
11087258
See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000737748.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (12)

Description

The p.Y315C pathogenic mutation (also known as c.944A>G), located in coding exon 7 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 944. The tyrosine at codon 315 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGD) located between transmembrane helices S5 and S6. This alteration has been seen in multiple unrelated individuals reported to have confirmed or suspected long QT syndrome, with variable expressivity in some cases (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Chen S et al. Clin Genet. 2003;63(4):273-82; Moss AJ et al. Circulation. 2007; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; 115(19):2481-9; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Bartos DC et al. Heart Rhythm. 2014;11(3):459-68). One study reported this alteration to result in a dominant negative effect on wild-type IKs current when expressed with wild-type channel in vitro (Bianchi L et al. Am J Physiol Heart Circ Physiol. 2000;279(6):H3003-11). Internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). In addition, another alteration affecting this codon (p.Y315S, c.944A>C) has also been associated with LQTS (Jongbloed RJ et al. Hum Mutat. 1999;13(4):301-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Dec 4, 2021

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