NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn) AND Congenital long QT syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 20, 2020
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:: RCV000057738.5

Allele description [Variation Report for NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn)]

NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn)

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.724G>A (p.Asp242Asn)

Other names:

p.D242N:GAC>AAC

HGVS:

NC_000011.10:g.2572053G>A
NG_008935.1:g.132063G>A
NM_000218.3:c.724G>AMANE SELECT
NM_001406836.1:c.724G>A
NM_001406837.1:c.454G>A
NM_181798.2:c.343G>A
NP_000209.2:p.Asp242Asn
NP_000209.2:p.Asp242Asn
NP_001393765.1:p.Asp242Asn
NP_001393766.1:p.Asp152Asn
NP_861463.1:p.Asp115Asn
NP_861463.1:p.Asp115Asn
LRG_287t1:c.724G>A
LRG_287t2:c.343G>A
LRG_287:g.132063G>A
LRG_287p1:p.Asp242Asn
LRG_287p2:p.Asp115Asn
NC_000011.9:g.2593283G>A
NM_000218.2:c.724G>A
NM_181798.1:c.343G>A
NR_040711.2:n.617G>A
P51787:p.Asp242Asn

Protein change:

D115N

Links:

UniProtKB: P51787#VAR_008940; dbSNP: rs199472712

NCBI 1000 Genomes Browser:

rs199472712

Molecular consequence:

NM_000218.3:c.724G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.724G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.454G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.343G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital long QT syndrome (RWS)
Synonyms:: Familial long QT syndrome; Romano-Ward syndrome; Ventricular fibrillation with prolonged QT interval
Identifiers:: MONDO: MONDO:0019171; MedGen: C1141890; Orphanet: 768; OMIM: PS192500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000089257	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 9799083, 15840476, 19716085, 17470695, 22581653
SCV004847826	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 20, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15840476, 25705178, 9799083, 17470695, 19716085, 28739325, 19490272, 23631430, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000089257

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

no classification provided

not provided

germline

literature only

PubMed (5)
[See all records that cite these PMIDs]

SCV004847826

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 20, 2020)

germline

clinical testing

PubMed (9)
[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, literature only

Citations

PubMed

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]

PMID:: 22581653
PMCID:: PMC4640174

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]

PMID:: 15840476

See all PubMed Citations (10)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089257.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9799083;PMID:15840476;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847826.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Asp242Asn variant in KCNQ1 has been reported in at least 4 individuals with long QT syndrome (LQTS; Itoh 1998 PMID: 9799083, Moss 2007 PMID:17470695, Jons 2009 PMID: 19490272), and in at least 6 individuals with suspected LQTS (Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085, Lieve 2013 PMID: 23631430). It is possible that there may be some overlap in the number of individuals from both groups. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 53090) and has been identified in 0.001% (1/112294 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Mousavi Nik 2015 PMID: 25705178, Moreno 2017 PMID: 28739325) and computational prediction tools and conservation are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting.

#	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 13, 2024

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