NM_000218.3(KCNQ1):c.1700T>C (p.Ile567Thr) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 2, 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:: RCV000046016.25

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1700T>C (p.Ile567Thr)]

NM_000218.3(KCNQ1):c.1700T>C (p.Ile567Thr)

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.1700T>C (p.Ile567Thr)

Other names:

p.I567T:ATT>ACT

HGVS:

NC_000011.10:g.2777000T>C
NG_008935.1:g.337010T>C
NM_000218.3:c.1700T>CMANE SELECT
NM_001406836.1:c.1604T>C
NM_001406837.1:c.1430T>C
NM_001406838.1:c.1160T>C
NM_181798.2:c.1319T>C
NP_000209.2:p.Ile567Thr
NP_000209.2:p.Ile567Thr
NP_001393765.1:p.Ile535Thr
NP_001393766.1:p.Ile477Thr
NP_001393767.1:p.Ile387Thr
NP_861463.1:p.Ile440Thr
NP_861463.1:p.Ile440Thr
LRG_287t1:c.1700T>C
LRG_287t2:c.1319T>C
LRG_287:g.337010T>C
LRG_287p1:p.Ile567Thr
LRG_287p2:p.Ile440Thr
NC_000011.9:g.2798230T>C
NM_000218.2:c.1700T>C
NM_181798.1:c.1319T>C
NR_040711.2:n.1593T>C
P51787:p.Ile567Thr

Protein change:

I387T

Links:

UniProtKB: P51787#VAR_075023; dbSNP: rs199472805

NCBI 1000 Genomes Browser:

rs199472805

Molecular consequence:

NM_000218.3:c.1700T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1604T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.1430T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.1160T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.1319T>C - 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
SCV000074029	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 2, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16414944, 19716085, 22429796, 23130128, 24372464, 17470695, 22456477, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000074029

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 2, 2024)

germline

clinical testing

PubMed (8)
[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

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S.

JAMA. 2005 Dec 21;294(23):2975-80.

PubMed [citation]

PMID:: 16414944

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 (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000074029.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 567 of the KCNQ1 protein (p.Ile567Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (LQTs) and/or Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 16414944, 19716085, 22429796, 23130128, 24372464). ClinVar contains an entry for this variant (Variation ID: 53007). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. This variant disrupts the p.Ile567 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17470695, 22456477). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: May 16, 2025

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