NM_000218.3(KCNQ1):c.1555C>T (p.Arg519Cys) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 2, 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:: RCV002514284.12

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1555C>T (p.Arg519Cys)]

NM_000218.3(KCNQ1):c.1555C>T (p.Arg519Cys)

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.1555C>T (p.Arg519Cys)

HGVS:

NC_000011.10:g.2768884C>T
NG_008935.1:g.328894C>T
NM_000218.3:c.1555C>TMANE SELECT
NM_001406836.1:c.1459C>T
NM_001406837.1:c.1285C>T
NM_001406838.1:c.1015C>T
NM_181798.2:c.1174C>T
NP_000209.2:p.Arg519Cys
NP_000209.2:p.Arg519Cys
NP_001393765.1:p.Arg487Cys
NP_001393766.1:p.Arg429Cys
NP_001393767.1:p.Arg339Cys
NP_861463.1:p.Arg392Cys
NP_861463.1:p.Arg392Cys
LRG_287t1:c.1555C>T
LRG_287t2:c.1174C>T
LRG_287:g.328894C>T
LRG_287p1:p.Arg519Cys
LRG_287p2:p.Arg392Cys
NC_000011.9:g.2790114C>T
NM_000218.2:c.1555C>T
NM_181798.1:c.1174C>T
NR_040711.2:n.1448C>T

Protein change:

R339C

Links:

dbSNP: rs199472787

NCBI 1000 Genomes Browser:

rs199472787

Molecular consequence:

NM_000218.3:c.1555C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1459C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.1285C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.1015C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.1174C>T - 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
SCV003476482	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12566525, 24190995, 28492532
SCV004836458	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12566525, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003476482

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 22, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004836458

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 2, 2023)

germline

clinical testing

PubMed (3)
[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	10	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Intracellular ATP binding is required to activate the slowly activating K+ channel I(Ks).

Li Y, Gao J, Lu Z, McFarland K, Shi J, Bock K, Cohen IS, Cui J.

Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18922-7. doi: 10.1073/pnas.1315649110. Epub 2013 Nov 4.

PubMed [citation]

PMID:: 24190995
PMCID:: PMC3839694

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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003476482.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 519 of the KCNQ1 protein (p.Arg519Cys). This variant is present in population databases (rs199472787, gnomAD 0.006%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 12566525). ClinVar contains an entry for this variant (Variation ID: 67037). 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 expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 24190995). 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, SCV004836458.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 519 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). This variant is found within a highly conserved C-terminus region (a.a. 509-575). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 12566525, Kostereva 2022 DOI: 10.35336/VA-2022-1-02). This variant has been identified in 11/251406 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		10	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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