NM_000218.3(KCNQ1):c.1022C>G (p.Ala341Gly) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 24, 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:: RCV002513746.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1022C>G (p.Ala341Gly)]

NM_000218.3(KCNQ1):c.1022C>G (p.Ala341Gly)

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.1022C>G (p.Ala341Gly)

Other names:

p.A341G:GCG>GGG

HGVS:

NC_000011.10:g.2583535C>G
NG_008935.1:g.143545C>G
NM_000218.3:c.1022C>GMANE SELECT
NM_001406836.1:c.1022C>G
NM_001406837.1:c.752C>G
NM_001406838.1:c.578C>G
NM_181798.2:c.641C>G
NP_000209.2:p.Ala341Gly
NP_000209.2:p.Ala341Gly
NP_001393765.1:p.Ala341Gly
NP_001393766.1:p.Ala251Gly
NP_001393767.1:p.Ala193Gly
NP_861463.1:p.Ala214Gly
NP_861463.1:p.Ala214Gly
LRG_287t1:c.1022C>G
LRG_287t2:c.641C>G
LRG_287:g.143545C>G
LRG_287p1:p.Ala341Gly
LRG_287p2:p.Ala214Gly
NC_000011.9:g.2604765C>G
NM_000218.2:c.1022C>G
NM_181798.1:c.641C>G
NR_040711.2:n.915C>G
P51787:p.Ala341Gly

Protein change:

A193G

Links:

UniProtKB: P51787#VAR_074985; dbSNP: rs12720459

NCBI 1000 Genomes Browser:

rs12720459

Molecular consequence:

NM_000218.3:c.1022C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1022C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.752C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.641C>G - 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
SCV003439770	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 24, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8528244, 15051636, 16246960, 16627448, 17984373, 22949429, 25634836, 19716085, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003439770

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 24, 2023)

germline

clinical testing

PubMed (9)
[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

Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.

Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT.

Nat Genet. 1996 Jan;12(1):17-23.

PubMed [citation]

PMID:: 8528244

Compound mutations: a common cause of severe long-QT syndrome.

Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC.

Circulation. 2004 Apr 20;109(15):1834-41. Epub 2004 Mar 29.

PubMed [citation]

PMID:: 15051636

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV003439770.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

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.Ala341 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 15051636, 16246960, 16627448, 17984373, 22949429, 25634836). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 67005). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 341 of the KCNQ1 protein (p.Ala341Gly).

#	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: Feb 20, 2024

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