NM_000218.3(KCNQ1):c.1553G>A (p.Arg518Gln) AND Long QT syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 29, 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:: RCV000148557.16

Allele description

NM_000218.3(KCNQ1):c.1553G>A (p.Arg518Gln)

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.1553G>A (p.Arg518Gln)

HGVS:

NC_000011.10:g.2768882G>A
NG_008935.1:g.328892G>A
NM_000218.3:c.1553G>AMANE SELECT
NM_001406836.1:c.1457G>A
NM_001406837.1:c.1283G>A
NM_001406838.1:c.1013G>A
NM_181798.2:c.1172G>A
NP_000209.2:p.Arg518Gln
NP_000209.2:p.Arg518Gln
NP_001393765.1:p.Arg486Gln
NP_001393766.1:p.Arg428Gln
NP_001393767.1:p.Arg338Gln
NP_861463.1:p.Arg391Gln
NP_861463.1:p.Arg391Gln
LRG_287t1:c.1553G>A
LRG_287t2:c.1172G>A
LRG_287:g.328892G>A
LRG_287p1:p.Arg518Gln
LRG_287p2:p.Arg391Gln
NC_000011.9:g.2790112G>A
NM_000218.2:c.1553G>A
NM_181798.1:c.1172G>A
NR_040711.2:n.1446G>A
P51787:p.Arg518Gln

Protein change:

R338Q

Links:

UniProtKB: P51787#VAR_075011; dbSNP: rs145974930

NCBI 1000 Genomes Browser:

rs145974930

Molecular consequence:

NM_000218.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.1283G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.1013G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.1172G>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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Saccharomyces cerevisiae S288C ribosomal 40S subunit protein S23A (RPS23A), part...
Saccharomyces cerevisiae S288C ribosomal 40S subunit protein S23A (RPS23A), partial mRNA
gi|398365760|ref|NM_001181247.3|

Nucleotide
Pyrenophora tritici-repentis GlcD, FAD-FMN-containing dehydrogenase (PtrM4_01817...
Pyrenophora tritici-repentis GlcD, FAD-FMN-containing dehydrogenase (PtrM4_018170), partial mRNA
gi|189190769|ref|XM_001931689.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190270	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV001540109	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 26159999, 29544605, 26546361, 16414944, 21511995, 24363352, 28492532
SCV004836457	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19716085, 26159999, 26546361, 29544605, 31994352, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190270

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV001540109

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004836457

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

PubMed (6)
[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	11	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S.

JAMA. 2005 Dec 21;294(23):2975-80.

PubMed [citation]

PMID:: 16414944

Detection of extra components of T wave by independent component analysis in congenital long-QT syndrome.

Horigome H, Ishikawa Y, Shiono J, Iwamoto M, Sumitomo N, Yoshinaga M.

Circ Arrhythm Electrophysiol. 2011 Aug;4(4):456-64. doi: 10.1161/CIRCEP.110.958827. Epub 2011 Apr 21. Erratum in: Circ Arrhythm Electrophysiol. 2011 Oct;4(5):e71.

PubMed [citation]

PMID:: 21511995

See all PubMed Citations (10)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Invitae, SCV001540109.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the KCNQ1 protein (p.Arg518Gln). This variant is present in population databases (rs145974930, gnomAD 0.005%). This missense change has been observed in individual(s) with sudden infant death syndrome and in individuals with QT intervals in the normal range (PMID: 26159999, 29544605). ClinVar contains an entry for this variant (Variation ID: 67036). 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%. Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 26546361). This variant disrupts the p.Arg518 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 21511995, 24363352; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV004836457.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces arginine with glutamine at codon 518 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not affect the ability of KCNQ1 protein to regulate renal ciliogenesis (PMID: 19716085, 26546361). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 29544605) and in several individuals referred for long QT syndrome genetic testing (PMID: 19716085, 26159999). Mean QTc interval of the carriers was not significantly different from that of non-carriers (PMID: 26159999). This variant has also been reported in one individual affected with cardiac arrest; however, the sibling who also carried the variant was asymptomatic (PMID: 31994352). This variant has been identified in 9/282772 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		11	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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