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NM_000218.3(KCNQ1):c.1893dup (p.Arg632fs) AND Long QT syndrome

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Jan 30, 2025
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:
RCV000046040.25

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1893dup (p.Arg632fs)]

NM_000218.3(KCNQ1):c.1893dup (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.1893dup (p.Arg632fs)
Other names:
KCNQ1, 1-BP INS; p.Arg632Glnfs*20
HGVS:
  • NC_000011.10:g.2847865dup
  • NC_000011.9:g.2869088_2869089insC
  • NG_008935.1:g.407875dup
  • NM_000218.3:c.1893dupMANE SELECT
  • NM_001406836.1:c.1797dup
  • NM_001406837.1:c.1623dup
  • NM_001406838.1:c.1353dup
  • NM_001406839.1:c.405dup
  • NM_181798.2:c.1512dup
  • NP_000209.2:p.Arg632fs
  • NP_001393765.1:p.Arg600Glnfs
  • NP_001393766.1:p.Arg542Glnfs
  • NP_001393767.1:p.Arg452Glnfs
  • NP_001393768.1:p.Arg136Glnfs
  • NP_861463.1:p.Arg505Glnfs
  • NP_861463.1:p.Arg505fs
  • LRG_287t2:c.1512dup
  • LRG_287:g.407875dup
  • LRG_287p2:p.Arg505fs
  • NC_000011.9:g.2869088_2869089insC
  • NC_000011.9:g.2869095_2869096insC
  • NC_000011.9:g.2869095dup
  • NC_000011.9:g.2869095dup
  • NM_000218.2:c.1893dupC
  • NM_000218.3:c.1893dup
  • NM_000218.3:c.1893dupCMANE SELECT
  • NM_181798.1:c.1512dup
  • NR_040711.2:n.1786dup
  • p.R632QfsX20
Protein change:
R505fs
Links:
OMIM: 607542.0025; dbSNP: rs397508104
NCBI 1000 Genomes Browser:
rs397508104
Molecular consequence:
  • NM_000218.3:c.1893dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406836.1:c.1797dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406837.1:c.1623dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406838.1:c.1353dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001406839.1:c.405dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_181798.2:c.1512dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
11

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
SCV000074053Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 30, 2025) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004836499All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Aug 8, 2024) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV005900415Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Aug 5, 2024) 		germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot provided143475not 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. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.

Neyroud N, Richard P, Vignier N, Donger C, Denjoy I, Demay L, Shkolnikova M, Pesce R, Chevalier P, Hainque B, Coumel P, Schwartz K, Guicheney P.

Circ Res. 1999 Feb 19;84(3):290-7.

PubMed [citation]
PMID:
10024302
See all PubMed Citations (18)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000074053.11

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

Description

This sequence change creates a premature translational stop signal (p.Arg632Glnfs*20) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the KCNQ1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with long QT syndrome, Jervell and Lange-Nielsen syndrome and recessive Romano–Ward syndrome (PMID: 10024302, 16981927, 19825999, 23098067, 23631430, 25187895). This variant is also known as 1893insC, insC1893–1894 (P631fs/19), 1893insC P631+19X and p.G629fs. ClinVar contains an entry for this variant (Variation ID: 53027). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects KCNQ1 function (PMID: 19825999). For these reasons, this variant has been 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, SCV004836499.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided11not providednot providedclinical testing PubMed (7)

Description

This variant inserts one nucleotide in exon 16 of the KCNQ1 gene, creating a frameshift in the last exon. This variant is also known as c.1893_1894insC and P631fs/19 in the literature. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. A functional study has shown that this variant causes protein trafficking defects, and the mutant protein is retained in the endoplasmic reticulum and unable to reach the cell surface (PMID: 19825999). As a result, the cells show severely decreased potassium currents (PMID: 19825999, 33498651). This variant has been reported in multiple individuals affected with monoallelic and biallelic forms of long QT syndrome (PMID: 10024302, 19825999, 23098067, 23631430, 25187895, 33498651). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown143475not providednot provided11not providednot providednot provided

From Molecular Genetics, Royal Melbourne Hospital, SCV005900415.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (15)

Description

This sequence change in KCNQ1 is a frameshift variant that may cause a premature stop codon, p.(Arg632Glnfs*20), that is predicted to escape nonsense-mediated decay and remove <10% of the protein in a gene where loss-of-function is an established disease mechanism (PMID: 11226272, 23098067, 26669661, 29532034). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.02% (14/86,106 alleles) in the South Asian population, consistent with a recessive disease. This variant has been detected compound heterozygous with a second pathogenic allele and homozygous in multiple individuals with long QT syndrome (mainly without deafness) and a recessive segregation with disease has been reported in one family (PMID: 16981927, 23098067, 23631430, 25187895, 32470535, 33498651). Heterozygous individuals have largely been reported as unaffected (PMID: 23158531, 30919684, 31696929, 32383558, 34691145). Functional studies suggest the variant only alters cardiac channel function in a homomeric state, supportive of a recessive inheritance trait (PMID: 33498651). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Moderate, PM3_VeryStrong, PP1, PS3_Supporting.

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

Last Updated: May 3, 2025