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

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 6, 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:: RCV000046039.18

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

NM_000218.3(KCNQ1):c.1893del (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:

Deletion

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.1893del (p.Arg632fs)

HGVS:

NC_000011.10:g.2847865del
NG_008935.1:g.407875del
NM_000218.3:c.1893delMANE SELECT
NM_001406836.1:c.1797delC
NM_001406837.1:c.1623delC
NM_001406838.1:c.1353delC
NM_001406839.1:c.405delC
NM_181798.2:c.1512delC
NP_000209.2:p.Arg632Glufs
NP_000209.2:p.Arg632fs
NP_000209.2:p.Arg632fs
NP_001393765.1:p.Arg600Glufs
NP_001393766.1:p.Arg542Glufs
NP_001393767.1:p.Arg452Glufs
NP_001393768.1:p.Arg136Glufs
NP_861463.1:p.Arg505Glufs
NP_861463.1:p.Arg505fs
LRG_287t1:c.1893del
LRG_287t2:c.1512del
LRG_287:g.407875del
LRG_287p1:p.Arg632fs
LRG_287p2:p.Arg505fs
NC_000011.9:g.2869089del
NC_000011.9:g.2869095del
NM_000218.2:c.1893del
NM_000218.2:c.1893delC
NM_181798.1:c.1512del
NR_040711.2:n.1786delC

Protein change:

R505fs

Links:

dbSNP: rs397508104

NCBI 1000 Genomes Browser:

rs397508104

Molecular consequence:

NM_000218.3:c.1893del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406836.1:c.1797delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406837.1:c.1623delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406838.1:c.1353delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406839.1:c.405delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_181798.2:c.1512delC - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

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

Recent activity

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mediator of RNA polymerase II transcription subunit [Arabidopsis thaliana]
mediator of RNA polymerase II transcription subunit [Arabidopsis thaliana]
gi|186478536|ref|NP_173029.2|

Protein
Homologene neighbors for GEO Profiles (Select 132375582) (0)
GEO Profiles
OGT O-linked N-acetylglucosamine (GlcNAc) transferase [Homo sapiens]
OGT O-linked N-acetylglucosamine (GlcNAc) transferase [Homo sapiens]
Gene ID:8473

Gene
Gene Links for GEO Profiles (Select 132350629) (1)
Gene
Related DataSets for GEO Profiles (Select 107964096) (1)
GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000074052	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9323054, 19862833, 16414944, 22739119, 28492532
SCV004836500	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Aug 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16414944, 22739119, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000074052

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2023)

germline

clinical testing

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

SCV004836500

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Aug 23, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical 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 (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000074052.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg632Glufs*34) 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). 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 individual(s) with long QT syndrome (PMID: 16414944, 22739119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53026). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004836500.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). 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 Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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