NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs) AND Cardiovascular phenotype

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 17, 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:: RCV000590377.8

Allele description [Variation Report for NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs)]

NM_000218.3(KCNQ1):c.573_577del (p.Arg192fs)

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.573_577del (p.Arg192fs)

Other names:

NP_000209.2:p.Arg518Ter

HGVS:

NC_000011.10:g.2570723_2570727del
NG_008935.1:g.130733_130737del
NM_000218.2:c.572_576del
NM_000218.3:c.573_577delMANE SELECT
NM_001406836.1:c.573_577delGCGCT
NM_001406837.1:c.303_307delGCGCT
NM_181798.2:c.192_196delGCGCT
NP_000209.2:p.Arg192Cysfs
NP_000209.2:p.Arg192fs
NP_000209.2:p.Arg192fs
NP_001393765.1:p.Arg192Cysfs
NP_001393766.1:p.Arg102Cysfs
NP_861463.1:p.Arg65Cysfs
NP_861463.1:p.Arg65fs
LRG_287t1:c.573_577del
LRG_287t2:c.192_196del
LRG_287:g.130733_130737del
LRG_287p1:p.Arg192fs
LRG_287p2:p.Arg65fs
NC_000011.9:g.2591950_2591954del
NC_000011.9:g.2591953_2591957del
NM_000218.2:c.572_576del
NM_000218.2:c.573_577del
NM_000218.2:c.573_577delGCGCT
NM_000218.3:c.573_577del
NM_181798.1:c.192_196del
NM_181798.1:c.192_196delGCGCT
NR_040711.2:n.466_470delGCGCT
p.Arg192CysfsX91
p.R192CfsX91

Protein change:

R192fs

Links:

dbSNP: rs397508118

NCBI 1000 Genomes Browser:

rs397508118

Molecular consequence:

NM_000218.3:c.573_577del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406836.1:c.573_577delGCGCT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406837.1:c.303_307delGCGCT - frameshift variant - [Sequence Ontology: SO:0001589]
NM_181798.2:c.192_196delGCGCT - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000695992	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 17, 2016)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23392653, 18452873, 10973849, 15840476, 9328483, 22677073, 22539601, 25991456, 11530100, 11140949 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000737838	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10560595, 10704188, 11530100, 22539601, 24666684, 9328483 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000695992

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 17, 2016)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000737838

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 17, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity.

Giudicessi JR, Ackerman MJ.

Circ Cardiovasc Genet. 2013 Apr;6(2):193-200. doi: 10.1161/CIRCGENETICS.112.964684. Epub 2013 Feb 7.

PubMed [citation]

PMID:: 23392653
PMCID:: PMC3683572

Prevalence of early-onset atrial fibrillation in congenital long QT syndrome.

Johnson JN, Tester DJ, Perry J, Salisbury BA, Reed CR, Ackerman MJ.

Heart Rhythm. 2008 May;5(5):704-9. doi: 10.1016/j.hrthm.2008.02.007. Epub 2008 Feb 8.

PubMed [citation]

PMID:: 18452873
PMCID:: PMC3940082

See all PubMed Citations (13)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695992.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: The KCNQ1 c.573_577delGCGCT (p.Arg192Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNQ1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 4/120312 control chromosomes at a frequency of 0.0000332, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). The variant is recurrently reported in patients with JLNS in homozygous as well as heterozygous state. The variant is also reported in heterozygous state in LQTS patients or in individuals suspected of LQTS diagnosis, in individuals with normal or borderline QTS prolongation, atrial fibrillation and sudden unexplained death, suggesting that clinical features associated with a heterozygous c.573_577delGCGCT variant are variable. Functional data are consistent with disease-causing role of this variant. It has also been reported as a probable founder/common mutation in Norway and Sweden causing JLNS. One clinical labs in ClinVar as well as reputable databases have classified it as pathogenic. Taken together, 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 Ambry Genetics, SCV000737838.6

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

Description

The c.573_577delGCGCT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of 5 nucleotides at positions 573 to 577, causing a translational frameshift with a predicted alternate stop codon (p.R192Cfs*91). This alteration has been described in several homozygous and compound heterozygous families with autosomal recessive Jervell and Lange-Nielsen syndrome, and haplotype analysis has suggested a founder mutation effect in Norway (Tranebjaerg L et al. Am J Med Genet. 1999;89:137-46). Among these families, this alteration also was detected in the heterozygous state in multiple unaffected relatives; however, in other studies, this alteration was reported in heterozygous individuals with autosomal dominant long QT syndrome (LQTS) (Ackerman MJ et al. Mayo Clin Proc.1999;74:1088-94; Anderson HN et al. Cardiol Young. 2015;25:376-9), suggesting co-segregation with incomplete penetrance. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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

Last Updated: May 12, 2024

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