NM_000218.3(KCNQ1):c.683+5G>A AND Long QT syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002267608.12

Allele description [Variation Report for NM_000218.3(KCNQ1):c.683+5G>A]

NM_000218.3(KCNQ1):c.683+5G>A

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.683+5G>A

HGVS:

NC_000011.10:g.2571408G>A
NG_008935.1:g.131418G>A
NM_000218.3:c.683+5G>AMANE SELECT
NM_001406836.1:c.683+5G>A
NM_001406837.1:c.413+5G>A
NM_001406838.1:c.478-12027G>A
NM_181798.2:c.302+5G>A
LRG_287t1:c.683+5G>A
LRG_287:g.131418G>A
NC_000011.9:g.2592638G>A
NM_000218.2:c.683+5G>A

Links:

dbSNP: rs397508122

NCBI 1000 Genomes Browser:

rs397508122

Molecular consequence:

NM_000218.3:c.683+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406836.1:c.683+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406837.1:c.413+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001406838.1:c.478-12027G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_181798.2:c.302+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

Condition(s)

Name:: Long QT syndrome 1 (LQT1)
Identifiers:: MONDO: MONDO:0100316; MedGen: C4551647; Orphanet: 101016; Orphanet: 768; OMIM: 192500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002549818	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002588741	Roden Lab, Vanderbilt University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 5, 2022)	unknown, not applicable	research, in vitro	PubMed (2) [See all records that cite these PMIDs] 25741868, 36197721
SCV004024170	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004183540	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies.

O'Neill MJ, Wada Y, Hall LD, Mitchell DW, Glazer AM, Roden DM.

Circ Genom Precis Med. 2022 Dec;15(6):e003782. doi: 10.1161/CIRCGEN.122.003782. Epub 2022 Oct 5.

PubMed [citation]

PMID:: 36197721
PMCID:: PMC9772980

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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002549818.2

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

Description

Criteria applied: PS3,PS4,PP3

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

From Roden Lab, Vanderbilt University Medical Center, SCV002588741.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (2)

Description

The KCNQ1 c.683+5G>A variant was observed in 3 cases of LQTS and was observed rarely in population databases (PMID: 32893267). A minigene assay provided experimental support for this prediction. Collectively, this evidence allows the classification of this variant as Likely Pathogenic.

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

From Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes, SCV004024170.1

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

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

From Baylor Genetics, SCV004183540.1

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

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

Last Updated: Oct 20, 2024

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