NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 29, 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:: RCV000617196.3

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)]

NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)

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.1096C>T (p.Arg366Trp)

Other names:

p.R366W:CGG>TGG

HGVS:

NC_000011.10:g.2585275C>T
NG_008935.1:g.145285C>T
NM_000218.3:c.1096C>TMANE SELECT
NM_001406837.1:c.826C>T
NM_181798.2:c.715C>T
NP_000209.2:p.Arg366Trp
NP_000209.2:p.Arg366Trp
NP_001393766.1:p.Arg276Trp
NP_861463.1:p.Arg239Trp
NP_861463.1:p.Arg239Trp
LRG_287t1:c.1096C>T
LRG_287t2:c.715C>T
LRG_287:g.145285C>T
LRG_287p1:p.Arg366Trp
LRG_287p2:p.Arg239Trp
NC_000011.9:g.2606505C>T
NM_000218.2:c.1096C>T
NM_181798.1:c.715C>T
NR_040711.2:n.989C>T
P51787:p.Arg366Trp

Protein change:

R239W

Links:

UniProtKB: P51787#VAR_008948; dbSNP: rs199473411

NCBI 1000 Genomes Browser:

rs199473411

Molecular consequence:

NM_000218.3:c.1096C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.715C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000737621	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jan 29, 2021)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 10973849, 15466642, 16556865, 19841300, 20196769, 20541041, 21499742, 22949429, 24357532, 24363352, 24606995, 25467552, 26063740, 29497013, 29790872, 31737537, 9693036 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000737621

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jan 29, 2021)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical 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

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

See all PubMed Citations (17)

Details of each submission

From Ambry Genetics, SCV000737621.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (17)

Description

The p.R366W pathogenic mutation (also known as c.1096C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1096. The arginine at codon 366 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in unrelated individuals reported to have long QT syndrome (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Choi G et al. Circulation. 2004;110(15):2119-24; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Giudicessi JR. et al. Circ Cardiovasc Genet. 2012;5(5):519-28; Torekov SS et al. Diabetes. 2014;63(4):1315-25). One in vitro study reported this alteration to result in impaired binding to calmodulin, altered ion channel kinetics, and reduced cell surface expression (Shamgar L et al. Circ Res. 2006;98(8):1055-63). In addition, other alterations affecting the same amino acid (p.R366P (c.1097G>C) and p.R366Q (c.1097G>A)) have also been reported in association with LQTS (Splawski I et al. Circulation. 2000;102(10):1178-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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