NM_000218.3(KCNQ1):c.569G>T (p.Arg190Leu) AND Cardiac arrhythmia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 1, 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:: RCV001841685.11

Allele description [Variation Report for NM_000218.3(KCNQ1):c.569G>T (p.Arg190Leu)]

NM_000218.3(KCNQ1):c.569G>T (p.Arg190Leu)

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.569G>T (p.Arg190Leu)

Other names:

p.R190L:CGG>CTG

HGVS:

NC_000011.10:g.2570719G>T
NG_008935.1:g.130729G>T
NM_000218.3:c.569G>TMANE SELECT
NM_001406836.1:c.569G>T
NM_001406837.1:c.299G>T
NM_181798.2:c.188G>T
NP_000209.2:p.Arg190Leu
NP_000209.2:p.Arg190Leu
NP_001393765.1:p.Arg190Leu
NP_001393766.1:p.Arg100Leu
NP_861463.1:p.Arg63Leu
NP_861463.1:p.Arg63Leu
LRG_287t1:c.569G>T
LRG_287t2:c.188G>T
LRG_287:g.130729G>T
LRG_287p1:p.Arg190Leu
LRG_287p2:p.Arg63Leu
NC_000011.9:g.2591949G>T
NM_000218.2:c.569G>T
NM_181798.1:c.188G>T
NR_040711.2:n.462G>T
P51787:p.Arg190Leu

Protein change:

R100L

Links:

UniProtKB: P51787#VAR_074945; dbSNP: rs120074178

NCBI 1000 Genomes Browser:

rs120074178

Molecular consequence:

NM_000218.3:c.569G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.569G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.299G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.188G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001352305	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19716085, 20138589, 24947509, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001352305

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 1, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

A new homozygous mutation of the KCNQ1 gene associated with both Romano-Ward and incomplete Jervell Lange-Nielsen syndromes in two sisters.

Kanovsky J, Novotny T, Kadlecova J, Gaillyova R.

Heart Rhythm. 2010 Apr;7(4):531-3. doi: 10.1016/j.hrthm.2009.11.034. Epub 2009 Dec 4. No abstract available.

PubMed [citation]

PMID:: 20138589

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001352305.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with leucine at codon 190 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has suggested that this missense variant may affect potassium channel function (PMID: 24947509). This variant has been reported in heterozygous state in an individual suspected of having long QT syndrome (PMID: 19716085). This variant has also been reported in homozygosity in two sisters, one affected with Jervell and Lange-Nielsen syndrome and the other one with Romano-Ward syndrome. Their heterozygous parents were asymptomatic but showed pathological QTs during the stress test (PMID: 20138589). This variant has been identified in 1/249462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg190Gln and p.Arg190Trp are known to be disease-causing (ClinVar variation ID: 3117, 53070), indicating that arginine at this position is important for KCNQ1 protein function. Based on available evidence, this variant is classified as Likely 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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