NM_000218.3(KCNQ1):c.1142G>A (p.Cys381Tyr) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 27, 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:: RCV002516853.4

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1142G>A (p.Cys381Tyr)]

NM_000218.3(KCNQ1):c.1142G>A (p.Cys381Tyr)

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.1142G>A (p.Cys381Tyr)

Other names:

p.C381Y:TGC>TAC

HGVS:

NC_000011.10:g.2587583G>A
NG_008935.1:g.147593G>A
NM_000218.3:c.1142G>AMANE SELECT
NM_001406836.1:c.1046G>A
NM_001406837.1:c.872G>A
NM_001406838.1:c.602G>A
NM_181798.2:c.761G>A
NP_000209.2:p.Cys381Tyr
NP_000209.2:p.Cys381Tyr
NP_001393765.1:p.Cys349Tyr
NP_001393766.1:p.Cys291Tyr
NP_001393767.1:p.Cys201Tyr
NP_861463.1:p.Cys254Tyr
NP_861463.1:p.Cys254Tyr
LRG_287t1:c.1142G>A
LRG_287t2:c.761G>A
LRG_287:g.147593G>A
LRG_287p1:p.Cys381Tyr
LRG_287p2:p.Cys254Tyr
NC_000011.9:g.2608813G>A
NM_000218.2:c.1142G>A
NM_181798.1:c.761G>A
NR_040711.2:n.1035G>A

Protein change:

C201Y

Links:

dbSNP: rs368507376

NCBI 1000 Genomes Browser:

rs368507376

Molecular consequence:

NM_000218.3:c.1142G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.602G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.761G>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
SCV003241122	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004836387	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25639344, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003241122

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 11, 2022)

germline

clinical testing

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

SCV004836387

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Apr 27, 2023)

germline

clinical testing

PubMed (2)
[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	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

Genetic variants in KCNE1, KCNQ1, and NOS1AP in sudden unexplained death during daily activities in Chinese Han population.

Huang J, Wang X, Hao B, Chen Y, Liu H, Quan L, Tang D, Sheng L, Li M, Huang E, Liu C, Luo B.

J Forensic Sci. 2015 Mar;60(2):351-6. doi: 10.1111/1556-4029.12687. Epub 2015 Jan 8. Erratum in: J Forensic Sci. 2018 Jan;63(1):349. doi: 10.1111/1556-4029.13725.

PubMed [citation]

PMID:: 25639344

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003241122.2

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 200844). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 381 of the KCNQ1 protein (p.Cys381Tyr). This variant is present in population databases (rs368507376, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions.

#	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, SCV004836387.1

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

Description

This missense variant replaces cysteine with tyrosine at codon 381 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden unexplained death (PMID: 25639344). This variant has been identified in 3/251142 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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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