NM_000218.3(KCNQ1):c.794C>A (p.Thr265Asn) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001983337.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.794C>A (p.Thr265Asn)]

NM_000218.3(KCNQ1):c.794C>A (p.Thr265Asn)

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.794C>A (p.Thr265Asn)

HGVS:

NC_000011.10:g.2572859C>A
NG_008935.1:g.132869C>A
NM_000218.3:c.794C>AMANE SELECT
NM_001406836.1:c.794C>A
NM_001406837.1:c.524C>A
NM_181798.2:c.413C>A
NP_000209.2:p.Thr265Asn
NP_000209.2:p.Thr265Asn
NP_001393765.1:p.Thr265Asn
NP_001393766.1:p.Thr175Asn
NP_861463.1:p.Thr138Asn
NP_861463.1:p.Thr138Asn
LRG_287t1:c.794C>A
LRG_287t2:c.413C>A
LRG_287:g.132869C>A
LRG_287p1:p.Thr265Asn
LRG_287p2:p.Thr138Asn
NC_000011.9:g.2594089C>A
NM_000218.2:c.794C>A
NM_181798.1:c.413C>A
NR_040711.2:n.687C>A

Protein change:

T138N

Links:

dbSNP: rs199472724

NCBI 1000 Genomes Browser:

rs199472724

Molecular consequence:

NM_000218.3:c.794C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.794C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.524C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.413C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002244081	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16542208, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002244081

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

QT interval prolongation associated with sibutramine treatment.

Harrison-Woolrych M, Clark DW, Hill GR, Rees MI, Skinner JR.

Br J Clin Pharmacol. 2006 Apr;61(4):464-9.

PubMed [citation]

PMID:: 16542208
PMCID:: PMC1885035

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002244081.3

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

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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr265 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 16542208), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 1461432). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 265 of the KCNQ1 protein (p.Thr265Asn).

#	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

Last Updated: Sep 29, 2024

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