NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn) AND Cardiac arrhythmia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003591645.1

Allele description [Variation Report for NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn)]

NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn)

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.604G>A (p.Asp202Asn)

Other names:

p.D202N:GAC>AAC

HGVS:

NC_000011.10:g.2570754G>A
NG_008935.1:g.130764G>A
NM_000218.3:c.604G>AMANE SELECT
NM_001406836.1:c.604G>A
NM_001406837.1:c.334G>A
NM_181798.2:c.223G>A
NP_000209.2:p.Asp202Asn
NP_000209.2:p.Asp202Asn
NP_001393765.1:p.Asp202Asn
NP_001393766.1:p.Asp112Asn
NP_861463.1:p.Asp75Asn
NP_861463.1:p.Asp75Asn
LRG_287t1:c.604G>A
LRG_287t2:c.223G>A
LRG_287:g.130764G>A
LRG_287p1:p.Asp202Asn
LRG_287p2:p.Asp75Asn
NC_000011.9:g.2591984G>A
NM_000218.2:c.604G>A
NM_181798.1:c.223G>A
NR_040711.2:n.497G>A

Protein change:

D112N

Links:

dbSNP: rs199472702

NCBI 1000 Genomes Browser:

rs199472702

Molecular consequence:

NM_000218.3:c.604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.334G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.223G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004358379	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 18, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12051962, 19716085, 20421371, 24372464, 31737537, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004358379

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 18, 2023)

germline

clinical testing

PubMed (7)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome.

Wang Z, Li H, Moss AJ, Robinson J, Zareba W, Knilans T, Bowles NE, Towbin JA.

Mol Genet Metab. 2002 Apr;75(4):308-16.

PubMed [citation]

PMID:: 12051962

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004358379.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant causes a G to A nucleotide substitution at the last nucleotide of exon 3 of the KCNQ1 gene and replaces aspartic acid with asparagine at codon 202 of the KCNQ1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing and computational prediction also suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain S3. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant impairs channel function by accelerating both activation and deactivation kinetics in transfected cells (PMID: 20421371). This variant has been reported in a few individuals affected with or suspected of having long QT syndrome (PMID: 19716085, 31737537, 32893267). This variant has also been observed in homozyous and compound heterozygous sate in two individuals affected with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 12051962, 24372464), indicating that this variant contributes to disease. This variant has been identified in 3/279614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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