NM_000218.3(KCNQ1):c.914G>A (p.Trp305Ter) AND Congenital long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 6, 2021
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:: RCV000826193.13

Allele description [Variation Report for NM_000218.3(KCNQ1):c.914G>A (p.Trp305Ter)]

NM_000218.3(KCNQ1):c.914G>A (p.Trp305Ter)

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.914G>A (p.Trp305Ter)

Other names:

p.Trp305X

HGVS:

NC_000011.10:g.2572979G>A
NG_008935.1:g.132989G>A
NM_000218.3:c.914G>AMANE SELECT
NM_001406836.1:c.914G>A
NM_001406837.1:c.644G>A
NM_181798.2:c.533G>A
NP_000209.2:p.Trp305Ter
NP_000209.2:p.Trp305Ter
NP_001393765.1:p.Trp305Ter
NP_001393766.1:p.Trp215Ter
NP_861463.1:p.Trp178Ter
NP_861463.1:p.Trp178Ter
LRG_287t1:c.914G>A
LRG_287t2:c.533G>A
LRG_287:g.132989G>A
LRG_287p1:p.Trp305Ter
LRG_287p2:p.Trp178Ter
NC_000011.9:g.2594209G>A
NM_000218.2:c.914G>A
NM_181798.1:c.533G>A
NR_040711.2:n.807G>A

Protein change:

W178*

Links:

dbSNP: rs120074186

NCBI 1000 Genomes Browser:

rs120074186

Molecular consequence:

NM_000218.3:c.914G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001406836.1:c.914G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001406837.1:c.644G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_181798.2:c.533G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000967743	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12702160, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967743

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 6, 2021)

germline

clinical testing

PubMed (2)
[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

KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death.

Chen S, Zhang L, Bryant RM, Vincent GM, Flippin M, Lee JC, Brown E, Zimmerman F, Rozich R, Szafranski P, Oberti C, Sterba R, Marangi D, Tchou PJ, Chung MK, Wang Q.

Clin Genet. 2003 Apr;63(4):273-82.

PubMed [citation]

PMID:: 12702160
PMCID:: PMC1579805

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967743.2

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

Description

The p.Trp305X variant in KCNQ1 has been reported in at least 1 individual with long QT syndrome (LQTS) and segregated with disease in at least 3 affected relatives (Chen et al. 2003). It has also been reported by other clinical laboratories in ClinVar (Variation ID 53124) and has been identified in 0.008% (2/24762) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 305, which is predicted to lead to a truncated or absent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also known as Romano-Ward syndrome) in the heterozygous state and with Jervell and Lange-Nielsen syndrome (JLNS) in the compound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, very low frequency in the general population, and predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PP1_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: Apr 20, 2024

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