NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp) AND Congenital long QT syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 24, 2017
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:: RCV000057551.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)]

NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)

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.1096C>T (p.Arg366Trp)

Other names:

p.R366W:CGG>TGG

HGVS:

NC_000011.10:g.2585275C>T
NG_008935.1:g.145285C>T
NM_000218.3:c.1096C>TMANE SELECT
NM_001406837.1:c.826C>T
NM_181798.2:c.715C>T
NP_000209.2:p.Arg366Trp
NP_000209.2:p.Arg366Trp
NP_001393766.1:p.Arg276Trp
NP_861463.1:p.Arg239Trp
NP_861463.1:p.Arg239Trp
LRG_287t1:c.1096C>T
LRG_287t2:c.715C>T
LRG_287:g.145285C>T
LRG_287p1:p.Arg366Trp
LRG_287p2:p.Arg239Trp
NC_000011.9:g.2606505C>T
NM_000218.2:c.1096C>T
NM_181798.1:c.715C>T
NR_040711.2:n.989C>T
P51787:p.Arg366Trp

Protein change:

R239W

Links:

UniProtKB: P51787#VAR_008948; dbSNP: rs199473411

NCBI 1000 Genomes Browser:

rs199473411

Molecular consequence:

NM_000218.3:c.1096C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.715C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000089070	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (11) [See all records that cite these PMIDs] 9693036, 10220146, 11668638, 14678125, 15466642, 15840476, 16937190, 19716085, 19841300, 10090529, 22581653
SCV000731642	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jul 24, 2017)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 19716085, 15466642, 9693036, 19841300, 16556865, 22949429, 9024139, 10973849, 24357532, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000089070

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

no classification provided

not provided

germline

literature only

PubMed (11)
[See all records that cite these PMIDs]

SCV000731642

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jul 24, 2017)

germline

clinical testing

PubMed (10)
[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	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants.

Larsen LA, Christiansen M, Vuust J, Andersen PS.

Hum Mutat. 1999;13(4):318-27.

PubMed [citation]

PMID:: 10220146

Automated mutation screening using dideoxy fingerprinting and capillary array electrophoresis.

Larsen LA, Johnson M, Brown C, Christiansen M, Frank-Hansen R, Vuust J, Andersen PS.

Hum Mutat. 2001 Nov;18(5):451-7.

PubMed [citation]

PMID:: 11668638

See all PubMed Citations (17)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089070.3

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

Description

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9693036;PMID:10220146;PMID:11668638;PMID:14678125;PMID:15466642;PMID:15840476;PMID:16937190;PMID:19716085;PMID:19841300;PMID:10090529). 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, SCV000731642.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (10)

Description

The p.Arg366Trp variant in KCNQ1 has been reported in >12 individuals with long QT syndrome (Splawski 1998, Choi 2004, Kapplinger 2009, Kapa 2009, Giudicessi 20 12, and Torekov 2014) and has also been reported by other clinical laboratories in ClinVar (Variation ID 52955). This variant was absent from large population s tudies. In vitro functional studies provide some evidence that the p.Arg366Trp v ariant may impact protein function (Shamgar 2006). Computational prediction tool s and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg366Trp variant meets criteria to be likely pathogenic for autosomal dominant long QT syndrome. ACMG/AMP Criteria applied: PM2, PS4_Mo derate, PS3_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: Oct 13, 2024

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