NM_000218.3(KCNQ1):c.1894dup (p.Arg632fs) AND Long QT syndrome

Clinical significance:Likely pathogenic (Last evaluated: Mar 15, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000459335.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1894dup (p.Arg632fs)]

NM_000218.3(KCNQ1):c.1894dup (p.Arg632fs)

Genes:
KCNQ1-AS1:KCNQ1 antisense RNA 1 [Gene - HGNC]
KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
11p15.4
Genomic location:
Preferred name:
NM_000218.3(KCNQ1):c.1894dup (p.Arg632fs)
HGVS:
  • NC_000011.10:g.2847866dup
  • NG_008935.1:g.407876dup
  • NM_000218.3:c.1894dupMANE SELECT
  • NM_181798.1:c.1513dup
  • NP_000209.2:p.Arg632fs
  • NP_861463.1:p.Arg505fs
  • LRG_287t2:c.1513dup
  • LRG_287:g.407876dup
  • LRG_287p2:p.Arg505fs
  • NC_000011.9:g.2869096dup
  • NM_000218.2:c.1894dupA
Protein change:
R505fs
Links:
dbSNP: rs397508105
NCBI 1000 Genomes Browser:
rs397508105
Molecular consequence:
  • NM_000218.3:c.1894dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_181798.1:c.1513dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000543307Invitaecriteria provided, single submitter
Likely pathogenic
(Mar 15, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000543307.2

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

Description

This sequence change inserts 1 nucleotide in exon 16 of the KCNQ1 mRNA (c.1894dupA), causing a frameshift at codon 632. This creates a premature translational stop signal in the last exon of the KCNQ1 mRNA (p.Arg632Lysfs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acids of the KCNQ1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNQ1-related disease. A different truncation in KCNQ1 nearly identical to this variant (c.1893delC, p.Arg632Glnfs*20) has been determined to be pathogenic (PMID: 10024302, 10973849, 19825999, 23098067, 23631430, 25187895). This suggests that deletion of this region of the KCNQ1 protein is causative of disease. In summary, this variant is a novel insertion that is similar to a previously described pathogenic insertion. This evidence indicates that the variant is pathogenic, but additional data is 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 25, 2021

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