NM_000218.3(KCNQ1):c.521G>A (p.Arg174His) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 16, 2023
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:: RCV002336182.3

Allele description [Variation Report for NM_000218.3(KCNQ1):c.521G>A (p.Arg174His)]

NM_000218.3(KCNQ1):c.521G>A (p.Arg174His)

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.521G>A (p.Arg174His)

HGVS:

NC_000011.10:g.2570671G>A
NG_008935.1:g.130681G>A
NM_000218.3:c.521G>AMANE SELECT
NM_001406836.1:c.521G>A
NM_001406837.1:c.251G>A
NM_181798.2:c.140G>A
NP_000209.2:p.Arg174His
NP_000209.2:p.Arg174His
NP_001393765.1:p.Arg174His
NP_001393766.1:p.Arg84His
NP_861463.1:p.Arg47His
NP_861463.1:p.Arg47His
LRG_287t1:c.521G>A
LRG_287t2:c.140G>A
LRG_287:g.130681G>A
LRG_287p1:p.Arg174His
LRG_287p2:p.Arg47His
NC_000011.9:g.2591901G>A
NM_000218.2:c.521G>A
NM_181798.1:c.140G>A
NR_040711.2:n.414G>A
P51787:p.Arg174His

Protein change:

R174H

Links:

UniProtKB: P51787#VAR_008939; dbSNP: rs199472697

NCBI 1000 Genomes Browser:

rs199472697

Molecular consequence:

NM_000218.3:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.140G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002642027	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10367071, 20486126, 27251404, 29532034, 30571187, 34505893 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002642027

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 16, 2023)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

[Congenital long QT syndrome. The value of genetics in prognostic evaluation].

Denjoy I, Lupoglazoff JM, Donger C, Berthet M, Richard P, Neyroud N, Villain E, Lucet V, Coumel P, Guicheney P.

Arch Mal Coeur Vaiss. 1999 May;92(5):557-63. French.

PubMed [citation]

PMID:: 10367071

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY system.

Allegue C, Gil R, Sanchez-Diz P, Torres M, Quintela I, Carracedo A, Brión M.

Electrophoresis. 2010 May;31(10):1648-55. doi: 10.1002/elps.201000022.

PubMed [citation]

PMID:: 20486126

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002642027.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.R174H variant (also known as c.521G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 521. The arginine at codon 174 is replaced by histidine, an amino acid with highly similar properties. This variant has been described in association with long QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004;43(5):826-30; Shimizu W et al. J. Am. Coll. Cardiol. 2004;44(1):117-25; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). Functional analysis suggests this alteration causes a dominant negative trafficking defect (Vanoye CG et al. Circ Genom Precis Med, 2018 11;11:e002345; Huang H et al. Sci Adv. 2018;4:eaar2631). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: May 1, 2024

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