NM_000218.3(KCNQ1):c.796del (p.Leu266fs) AND Long QT syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 13, 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:: RCV001038095.10

Allele description [Variation Report for NM_000218.3(KCNQ1):c.796del (p.Leu266fs)]

NM_000218.3(KCNQ1):c.796del (p.Leu266fs)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.796del (p.Leu266fs)

HGVS:

NC_000011.10:g.2572861del
NG_008935.1:g.132871del
NM_000218.3:c.796delMANE SELECT
NM_001406836.1:c.796delC
NM_001406837.1:c.526delC
NM_181798.2:c.415delC
NP_000209.2:p.Leu266Cysfs
NP_000209.2:p.Leu266fs
NP_000209.2:p.Leu266fs
NP_001393765.1:p.Leu266Cysfs
NP_001393766.1:p.Leu176Cysfs
NP_861463.1:p.Leu139Cysfs
NP_861463.1:p.Leu139fs
LRG_287t1:c.796del
LRG_287t2:c.415del
LRG_287:g.132871del
LRG_287p1:p.Leu266fs
LRG_287p2:p.Leu139fs
NC_000011.9:g.2594089del
NC_000011.9:g.2594091del
NM_000218.2:c.796del
NM_000218.2:c.796delC
NM_181798.1:c.415del
NR_040711.2:n.689delC
p.L266CfsX23

Protein change:

L139fs

Links:

dbSNP: rs397508125

NCBI 1000 Genomes Browser:

rs397508125

Molecular consequence:

NM_000218.3:c.796del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406836.1:c.796delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406837.1:c.526delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_181798.2:c.415delC - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001201542	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9323054, 19862833, 16414944, 19716085, 28492532
SCV004825827	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16414944, 19716085, 22956155, 23631430, 34319147, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001201542

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 13, 2024)

germline

clinical testing

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

SCV004825827

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 16, 2023)

germline

clinical testing

PubMed (6)
[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 (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001201542.5

#	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.Leu266Cysfs*23) 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 (rs397508125, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with long QT syndrome or referred for long QT syndrome testing (PMID: 16414944, 19716085). ClinVar contains an entry for this variant (Variation ID: 53107). 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, SCV004825827.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 19716085, 23631430, 22956155, 34319147, 16414944). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

#	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: Sep 29, 2024

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