NM_181798.1(KCNQ1):c.416T>G (p.Leu139Arg) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Sep 23, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001205787.2

Allele description [Variation Report for NM_181798.1(KCNQ1):c.416T>G (p.Leu139Arg)]

NM_181798.1(KCNQ1):c.416T>G (p.Leu139Arg)

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_181798.1(KCNQ1):c.416T>G (p.Leu139Arg)
HGVS:
  • NC_000011.10:g.2572862T>G
  • NG_008935.1:g.132872T>G
  • NM_000218.2:c.797T>G
  • NM_181798.1:c.416T>G
  • NP_000209.2:p.Leu266Arg
  • NP_861463.1:p.Leu139Arg
  • LRG_287t1:c.797T>G
  • LRG_287t2:c.416T>G
  • LRG_287:g.132872T>G
  • LRG_287p1:p.Leu266Arg
  • LRG_287p2:p.Leu139Arg
  • NC_000011.9:g.2594092T>G
Protein change:
L139R
Links:
dbSNP: rs199473460
NCBI 1000 Genomes Browser:
rs199473460
Molecular consequence:
  • NM_000218.2:c.797T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.1:c.416T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976; OMIM: PS192500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001377062Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 23, 2020)
germlineclinical testing

PubMed (7)
[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

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]
PMID:
22949429
PMCID:
PMC3705705

Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.

Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, McNitt S.

Circulation. 2007 May 15;115(19):2481-9. Epub 2007 Apr 30.

PubMed [citation]
PMID:
17470695
PMCID:
PMC3332528
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001377062.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces leucine with arginine at codon 266 of the KCNQ1 protein (p.Leu266Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with long QT syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 393006). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Leu266 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22949429, 17470695, 17905336, 21451124, 1467812, 21118729). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: Oct 7, 2021

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