NM_000218.3(KCNQ1):c.1355G>A (p.Arg452Gln) AND Long QT syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000297971.24

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1355G>A (p.Arg452Gln)]

NM_000218.3(KCNQ1):c.1355G>A (p.Arg452Gln)

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.1355G>A (p.Arg452Gln)

Other names:

p.R452Q:CGG>CAG

HGVS:

NC_000011.10:g.2588816G>A
NG_008935.1:g.148826G>A
NM_000218.3:c.1355G>AMANE SELECT
NM_001406836.1:c.1259G>A
NM_001406837.1:c.1085G>A
NM_001406838.1:c.815G>A
NM_181798.2:c.974G>A
NP_000209.2:p.Arg452Gln
NP_000209.2:p.Arg452Gln
NP_001393765.1:p.Arg420Gln
NP_001393766.1:p.Arg362Gln
NP_001393767.1:p.Arg272Gln
NP_861463.1:p.Arg325Gln
NP_861463.1:p.Arg325Gln
LRG_287t1:c.1355G>A
LRG_287t2:c.974G>A
LRG_287:g.148826G>A
LRG_287p1:p.Arg452Gln
LRG_287p2:p.Arg325Gln
NC_000011.9:g.2610046G>A
NM_000218.2:c.1355G>A
NM_181798.1:c.974G>A
NR_040711.2:n.1248G>A

Protein change:

R272Q

Links:

dbSNP: rs145229963

NCBI 1000 Genomes Browser:

rs145229963

Molecular consequence:

NM_000218.3:c.1355G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1259G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.1085G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000370299	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Uncertain significance (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000543296	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26318259, 28492532
SCV004836427	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	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

SCV000370299

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Uncertain significance
(Jun 14, 2016)

germline

clinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000543296

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 2, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004836427

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

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	22	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1.

Ruwald MH, Xu Parks X, Moss AJ, Zareba W, Baman J, McNitt S, Kanters JK, Shimizu W, Wilde AA, Jons C, Lopes CM.

Heart Rhythm. 2016 Jan;13(1):122-31. doi: 10.1016/j.hrthm.2015.08.033. Epub 2015 Aug 28.

PubMed [citation]

PMID:: 26318259
PMCID:: PMC4743743

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

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000370299.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000543296.9

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 452 of the KCNQ1 protein (p.Arg452Gln). This variant is present in population databases (rs145229963, gnomAD 0.02%). This missense change has been observed in individual(s) with KCNQ1-related conditions (PMID: 26318259). ClinVar contains an entry for this variant (Variation ID: 67030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. 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.

#	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, SCV004836427.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces arginine with glutamine at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 31/281090 chromosomes 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		22	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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