NM_000218.3(KCNQ1):c.804C>A (p.Ile268=) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 3, 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:: RCV002050342.9

Allele description [Variation Report for NM_000218.3(KCNQ1):c.804C>A (p.Ile268=)]

NM_000218.3(KCNQ1):c.804C>A (p.Ile268=)

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.804C>A (p.Ile268=)

HGVS:

NC_000011.10:g.2572869C>A
NG_008935.1:g.132879C>A
NM_000218.3:c.804C>AMANE SELECT
NM_001406836.1:c.804C>A
NM_001406837.1:c.534C>A
NM_001406838.1:c.478-10566C>A
NM_181798.2:c.423C>A
NP_000209.2:p.Ile268=
NP_000209.2:p.Ile268=
NP_001393765.1:p.Ile268=
NP_001393766.1:p.Ile178=
NP_861463.1:p.Ile141=
NP_861463.1:p.Ile141=
LRG_287t1:c.804C>A
LRG_287t2:c.423C>A
LRG_287:g.132879C>A
LRG_287p1:p.Ile268=
LRG_287p2:p.Ile141=
NC_000011.9:g.2594099C>A
NM_000218.2:c.804C>A
NM_181798.1:c.423C>A
NR_040711.2:n.697C>A

Links:

dbSNP: rs373227792

NCBI 1000 Genomes Browser:

rs373227792

Molecular consequence:

NM_001406838.1:c.478-10566C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000218.3:c.804C>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001406836.1:c.804C>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001406837.1:c.534C>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_181798.2:c.423C>A - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002317689	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004816616	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 3, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002317689

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 15, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004816616

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 3, 2023)

germline

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	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002317689.3

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

Description

This sequence change affects codon 268 of the KCNQ1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCNQ1 protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with KCNQ1-related conditions. This variant is not present in population databases (ExAC no frequency).

#	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 All of Us Research Program, National Institutes of Health, SCV004816616.1

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

Description

This synonymous variant does not change the amino acid sequence of the KCNQ1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNQ1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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