NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 27, 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:: RCV000588586.11

Allele description [Variation Report for NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)]

NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)

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.502G>A (p.Gly168Arg)

HGVS:

NC_000011.10:g.2570652G>A
NG_008935.1:g.130662G>A
NM_000218.3:c.502G>AMANE SELECT
NM_001406836.1:c.502G>A
NM_001406837.1:c.232G>A
NM_181798.2:c.121G>A
NP_000209.2:p.Gly168Arg
NP_000209.2:p.Gly168Arg
NP_001393765.1:p.Gly168Arg
NP_001393766.1:p.Gly78Arg
NP_861463.1:p.Gly41Arg
NP_861463.1:p.Gly41Arg
LRG_287t1:c.502G>A
LRG_287t2:c.121G>A
LRG_287:g.130662G>A
LRG_287p1:p.Gly168Arg
LRG_287p2:p.Gly41Arg
NC_000011.9:g.2591882G>A
NM_000218.2:c.502G>A
NM_181798.1:c.121G>A
NR_040711.2:n.395G>A
P51787:p.Gly168Arg
p.G168R

Protein change:

G168R

Links:

UniProtKB: P51787#VAR_001516; dbSNP: rs179489

NCBI 1000 Genomes Browser:

rs179489

Molecular consequence:

NM_000218.3:c.502G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.502G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.121G>A - 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
SCV000736265	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Aug 27, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10973849, 15051636, 17091796, 19716085, 20186784, 22949429, 29952348, 31484877, 33256261, 9386136, 9693036 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000736265

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Aug 27, 2021)

germline

clinical testing

PubMed (11)
[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

Compound mutations: a common cause of severe long-QT syndrome.

Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC.

Circulation. 2004 Apr 20;109(15):1834-41. Epub 2004 Mar 29.

PubMed [citation]

PMID:: 15051636

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000736265.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

The p.G168R pathogenic mutation (also known as c.502G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 502. The glycine at codon 168 is replaced by arginine, an amino acid with dissimilar properties, and is located in the S2 transmembrane region of the protein. This alteration, and another nucleotide substitution resulting in the same amino acid change (c.502G>C), has been detected in multiple unrelated, heterozygous individuals reported to have long QT syndrome (LQTS), has been reported to segregate with LQTS in multiple families, and has been reported in the homozygous and compound heterozygous states in individuals with Jervell and Lange-Nielsen syndrome (Donger C et al. Circulation. 1997;96(9):2778-81; Splawski et al. Genomics. 1998;51(1):86-97; Splawski I et al. Circulation. 2000;102(10):1178-85; Márquez MF et al. Arch Cardiol Mex. 2006;76(3):257-62; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Summers KM et al. Am J Med Genet. 2010;152A(3):613-21; Vyas B. Am. J Med Genet A. 2016;170(6):1510-9; Sato A et al. Int Heart J. 2019 Sep;60(5):1206-1210; Lorca R et al. J Clin Med. 2020 Nov;9(12)). This alteration has been reported to result in loss of ion channel function in an in vitro assay (Westenskow P et al. Circulation. 2004;109(15):1834-41). 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.

#	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: Apr 20, 2024

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