NM_000218.3(KCNQ1):c.704T>A (p.Ile235Asn) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 18, 2022
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:: RCV000046108.16

Allele description [Variation Report for NM_000218.3(KCNQ1):c.704T>A (p.Ile235Asn)]

NM_000218.3(KCNQ1):c.704T>A (p.Ile235Asn)

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.704T>A (p.Ile235Asn)

HGVS:

NC_000011.10:g.2572033T>A
NG_008935.1:g.132043T>A
NM_000218.3:c.704T>AMANE SELECT
NM_001406836.1:c.704T>A
NM_001406837.1:c.434T>A
NM_181798.2:c.323T>A
NP_000209.2:p.Ile235Asn
NP_000209.2:p.Ile235Asn
NP_001393765.1:p.Ile235Asn
NP_001393766.1:p.Ile145Asn
NP_861463.1:p.Ile108Asn
NP_861463.1:p.Ile108Asn
LRG_287t1:c.704T>A
LRG_287t2:c.323T>A
LRG_287:g.132043T>A
LRG_287p1:p.Ile235Asn
LRG_287p2:p.Ile108Asn
NC_000011.9:g.2593263T>A
NM_000218.2:c.704T>A
NM_181798.1:c.323T>A
NR_040711.2:n.597T>A
P51787:p.Ile235Asn

Protein change:

I108N

Links:

UniProtKB: P51787#VAR_068293; dbSNP: rs199472710

NCBI 1000 Genomes Browser:

rs199472710

Molecular consequence:

NM_000218.3:c.704T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.704T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.434T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000074121	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 18, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19590188, 18452873, 22949429, 24269949, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000074121

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 18, 2022)

germline

clinical testing

PubMed (5)
[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

Long QT syndrome-associated mutations in the voltage sensor of I(Ks) channels.

Henrion U, Strutz-Seebohm N, Duszenko M, Lang F, Seebohm G.

Cell Physiol Biochem. 2009;24(1-2):11-6. doi: 10.1159/000227828. Epub 2009 Jul 1.

PubMed [citation]

PMID:: 19590188

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 (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000074121.7

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 19590188, 24269949). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 53088). This missense change has been observed in individuals with long QT syndrome (PMID: 18452873, 22949429, 24269949). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 235 of the KCNQ1 protein (p.Ile235Asn).

#	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: Nov 3, 2024

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