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NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter) AND Long QT syndrome

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Jan 24, 2024
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:
RCV000046003.21

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter)]

NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter)

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.1588C>T (p.Gln530Ter)
Other names:
p.Q530*:CAG>TAG; p.Gln530*
HGVS:
  • NC_000011.10:g.2768917C>T
  • NG_008935.1:g.328927C>T
  • NM_000218.3:c.1588C>TMANE SELECT
  • NM_001406836.1:c.1492C>T
  • NM_001406837.1:c.1318C>T
  • NM_001406838.1:c.1048C>T
  • NM_181798.2:c.1207C>T
  • NP_000209.2:p.Gln530Ter
  • NP_000209.2:p.Gln530Ter
  • NP_001393765.1:p.Gln498Ter
  • NP_001393766.1:p.Gln440Ter
  • NP_001393767.1:p.Gln350Ter
  • NP_861463.1:p.Gln403Ter
  • NP_861463.1:p.Gln403Ter
  • LRG_287t1:c.1588C>T
  • LRG_287t2:c.1207C>T
  • LRG_287:g.328927C>T
  • LRG_287p1:p.Gln530Ter
  • LRG_287p2:p.Gln403Ter
  • NC_000011.9:g.2790147C>T
  • NM_000218.2:c.1588C>T
  • NM_181798.1:c.1207C>T
  • NR_040711.2:n.1481C>T
Protein change:
Q350*
Links:
dbSNP: rs397508097
NCBI 1000 Genomes Browser:
rs397508097
Molecular consequence:
  • NM_000218.3:c.1588C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001406836.1:c.1492C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001406837.1:c.1318C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001406838.1:c.1048C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_181798.2:c.1207C>T - nonsense - [Sequence Ontology: SO:0001587]
Observations:
5

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
SCV000074016Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 24, 2024) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001360700Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Sep 25, 2019) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV004836460All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Dec 15, 2023) 		germlineclinical testing

PubMed (16)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown5not providednot provided108544not providedclinical testing

Citations

PubMed

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

The genetic basis of long QT and short QT syndromes: a mutation update.

Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M.

Hum Mutat. 2009 Nov;30(11):1486-511. doi: 10.1002/humu.21106. Review.

PubMed [citation]
PMID:
19862833
See all PubMed Citations (23)

Details of each submission

From Invitae, SCV000074016.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change creates a premature translational stop signal (p.Gln530*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is present in population databases (rs397508097, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 11530100, 14510661, 14678125, 15051636, 19716085, 22629021, 23392653, 24606995, 24912595). ClinVar contains an entry for this variant (Variation ID: 52996). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360700.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: KCNQ1 c.1588C>T (p.Gln530X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 2.8e-05 in 251292 control chromosomes (gnomAD). c.1588C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome as well as Lange-Nielsen Syndrome (eg. Itoh_2016, Mullally_2013, Tranebjaerg_1999). These data indicate that the variant is very likely to be associated with disease. Functional studies showed the variant did not yield any detectable potassium channel current (Mousavi Nik_2015). Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From All of Us Research Program, National Institutes of Health, SCV004836460.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (16)

Description

The c.1588C>T (p.Gln530*) variant of the KCNQ1 gene creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been identified in heterozygous, compound heterozygous or homozygous status in numerous individuals (>20) with dominant Long QT syndrome as well as recessive Jervell and Lange-Nielsen Syndrome (PMID:10973849, 23174487, 26669661, 11530100, 15051636, 14678125, 18752142, 23392653, 25705178). Loss of function variants are known to be pathogenic for KCNQ1 (PMID: 26669661, 29532034, 23098067). In-vitro assays using Chinese Hamster Ovary cells transfected with mutant plasmid and Xenopus laevis oocyte studies suggest that this variant causes defective trafficking to the cell membrane and non-functional potassium channel (PMID: 15051636, 24912595, 25705178). Truncating variants downstream of this variant are reported in individuals with Long QT syndrome (PMID:19841300, 27871843, 19716085). This variant is found to be rare (7/251292) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 52996). Therefore, the c.1588C>T (p.Gln530*) variant in the KCNQ1 gene is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided5not providednot providednot provided

Last Updated: Aug 18, 2024