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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:
RCV002513746.3

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003439770Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Jun 24, 2023)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003439770.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024