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NM_000218.3(KCNQ1):c.921+1G>T AND Long QT syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Dec 11, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001377884.10

Allele description [Variation Report for NM_000218.3(KCNQ1):c.921+1G>T]

NM_000218.3(KCNQ1):c.921+1G>T

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.921+1G>T
HGVS:
  • NC_000011.10:g.2572987G>T
  • NG_008935.1:g.132997G>T
  • NM_000218.3:c.921+1G>TMANE SELECT
  • NM_001406836.1:c.921+1G>T
  • NM_001406837.1:c.651+1G>T
  • NM_001406838.1:c.478-10448G>T
  • NM_181798.2:c.540+1G>T
  • LRG_287t1:c.921+1G>T
  • LRG_287:g.132997G>T
  • NC_000011.9:g.2594217G>T
  • NM_000218.2:c.921+1G>T
Links:
dbSNP: rs397508130
NCBI 1000 Genomes Browser:
rs397508130
Molecular consequence:
  • NM_001406838.1:c.478-10448G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000218.3:c.921+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406836.1:c.921+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406837.1:c.651+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_181798.2:c.540+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001575331Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Mar 26, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004840116All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Dec 11, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.

Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T, Blanar MA.

Circulation. 1997 Sep 16;96(6):1733-6.

PubMed [citation]
PMID:
9323054
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575331.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 53126). Disruption of this splice site has been observed in individual(s) with clinical features of long QT syndrome and/or Jervell and Lange-Nielsen syndrome (PMID: 10973849; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 of the KCNQ1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833).

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

From All of Us Research Program, National Institutes of Health, SCV004840116.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The c.921+1G>T variant in the KCNQ1 gene is located at the canonical donor splice site in intron 6 and is predicted to disrupt mRNA splicing resulting in an absent or aberrant protein product (SpliceAI score: 1.00). This variant has been reported in at least one individual with long QT syndrome (PMID:10973849). Loss-of-function variants are a known disease mechanism of long QT syndrome due to defects in the KCNQ1 gene (PMID:19862833). This variant is reported in ClinVar (ID: 53126). This variant is absent in the general population database, gnomAD. Therefore, the c.921+1G>T variant in the KCNQ1 gene is classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024