NM_000218.3(KCNQ1):c.726C>A (p.Asp242Glu) AND Long QT syndrome

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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
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:: RCV000823765.7

Allele description

NM_000218.3(KCNQ1):c.726C>A (p.Asp242Glu)

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.726C>A (p.Asp242Glu)

HGVS:

NC_000011.10:g.2572055C>A
NG_008935.1:g.132065C>A
NM_000218.3:c.726C>AMANE SELECT
NM_001406836.1:c.726C>A
NM_001406837.1:c.456C>A
NM_181798.2:c.345C>A
NP_000209.2:p.Asp242Glu
NP_000209.2:p.Asp242Glu
NP_001393765.1:p.Asp242Glu
NP_001393766.1:p.Asp152Glu
NP_861463.1:p.Asp115Glu
NP_861463.1:p.Asp115Glu
LRG_287t1:c.726C>A
LRG_287t2:c.345C>A
LRG_287:g.132065C>A
LRG_287p1:p.Asp242Glu
LRG_287p2:p.Asp115Glu
NC_000011.9:g.2593285C>A
NM_000218.2:c.726C>A
NM_181798.1:c.345C>A
NR_040711.2:n.619C>A

Protein change:

D115E

Links:

dbSNP: rs1589957756

NCBI 1000 Genomes Browser:

rs1589957756

Molecular consequence:

NM_000218.3:c.726C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.726C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.456C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.345C>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
SCV000964635	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31737537, 9799083, 19490272, 25705178, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000964635

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (5)
[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

Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.

Marschall C, Moscu-Gregor A, Klein HG.

Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298. doi: 10.21037/cdt.2019.06.06.

PubMed [citation]

PMID:: 31737537
PMCID:: PMC6837920

Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome.

Itoh T, Tanaka T, Nagai R, Kikuchi K, Ogawa S, Okada S, Yamagata S, Yano K, Yazaki Y, Nakamura Y.

Hum Genet. 1998 Sep;103(3):290-4.

PubMed [citation]

PMID:: 9799083

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000964635.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense change has been observed in individual(s) with KCNQ1-related conditions (PMID: 31737537). 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.Asp242 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9799083, 19490272, 25705178; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 665471). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 242 of the KCNQ1 protein (p.Asp242Glu).

#	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: May 1, 2024

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