NM_000218.3(KCNQ1):c.1556G>A (p.Arg519His) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 26, 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:: RCV001841670.11

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1556G>A (p.Arg519His)]

NM_000218.3(KCNQ1):c.1556G>A (p.Arg519His)

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.1556G>A (p.Arg519His)

HGVS:

NC_000011.10:g.2768885G>A
NG_008935.1:g.328895G>A
NM_000218.3:c.1556G>AMANE SELECT
NM_001406836.1:c.1460G>A
NM_001406837.1:c.1286G>A
NM_001406838.1:c.1016G>A
NM_181798.2:c.1175G>A
NP_000209.2:p.Arg519His
NP_000209.2:p.Arg519His
NP_001393765.1:p.Arg487His
NP_001393766.1:p.Arg429His
NP_001393767.1:p.Arg339His
NP_861463.1:p.Arg392His
NP_861463.1:p.Arg392His
LRG_287t1:c.1556G>A
LRG_287t2:c.1175G>A
LRG_287:g.328895G>A
LRG_287p1:p.Arg519His
LRG_287p2:p.Arg392His
NC_000011.9:g.2790115G>A
NM_000218.2:c.1556G>A
NM_181798.1:c.1175G>A
NR_040711.2:n.1449G>A

Protein change:

R339H

Links:

dbSNP: rs199472788

NCBI 1000 Genomes Browser:

rs199472788

Molecular consequence:

NM_000218.3:c.1556G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.1286G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.1016G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.1175G>A - 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
SCV001355442	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 26, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14661677, 19841300, 26118460, 32893267, 34930020, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001355442

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 26, 2023)

germline

clinical testing

PubMed (6)
[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

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.

Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME.

Mayo Clin Proc. 2003 Dec;78(12):1479-87.

PubMed [citation]

PMID:: 14661677

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001355442.3

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

Description

This missense variant replaces arginine with histidine at codon 519 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). This variant is found within a highly conserved region of the c-terminal cytoplasmic domain. Rare nontruncating variants in this region (a.a. 509-575) have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction in channel peak current density in transfected cells (PMID: 34930020). This variant has been reported in three unrelated individuals affected with long QT syndrome (PMID: 26118460), as well as in two healthy individuals (PMID: 19841300, 14661677). This variant has been identified in 7/282764 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Oct 26, 2024

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