NM_181798.1(KCNQ1):c.584C>T (p.Thr195Met) AND Long QT syndrome

Clinical significance:Pathogenic (Last evaluated: Aug 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000190213.6

Allele description [Variation Report for NM_181798.1(KCNQ1):c.584C>T (p.Thr195Met)]

NM_181798.1(KCNQ1):c.584C>T (p.Thr195Met)

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_181798.1(KCNQ1):c.584C>T (p.Thr195Met)
Other names:
p.T322M:ACG>ATG
HGVS:
  • NC_000011.10:g.2583478C>T
  • NG_008935.1:g.143488C>T
  • NM_000218.2:c.965C>T
  • NM_181798.1:c.584C>T
  • NP_000209.2:p.Thr322Met
  • NP_861463.1:p.Thr195Met
  • LRG_287t1:c.965C>T
  • LRG_287t2:c.584C>T
  • LRG_287:g.143488C>T
  • LRG_287p1:p.Thr322Met
  • LRG_287p2:p.Thr195Met
  • NC_000011.9:g.2604708C>T
  • P51787:p.Thr322Met
Protein change:
T195M
Links:
UniProtKB: P51787#VAR_074692; dbSNP: rs199472755
NCBI 1000 Genomes Browser:
rs199472755
Molecular consequence:
  • NM_000218.2:c.965C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.1:c.584C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976; OMIM: PS192500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000074196Invitaecriteria provided, single submitter
Pathogenic
(Aug 9, 2020)
germlineclinical testing

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

SCV000222064Medical Research Institute,Tokyo Medical and Dental University

See additional submitters

no assertion criteria providedLikely pathogenicgermlineresearch

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.

Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, McNitt S.

Circulation. 2007 May 15;115(19):2481-9. Epub 2007 Apr 30.

PubMed [citation]
PMID:
17470695
PMCID:
PMC3332528
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000074196.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces threonine with methionine at codon 322 of the KCNQ1 protein (p.Thr322Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This sequence change has been reported in the literature and is not currently found in any individuals from the population databases (rs199472755, no frequency). This sequence change has been reported in at least five unrelated patients with long QT syndrome (PMID: 16414944, 17470695, 19716085). In addition, the p.Thr322Met sequence change was observed in the homozygous state in two Jervell-Lange Nielsen patients in a family in PMID: 18400097. Heterozgous carriers of this sequence change in this family had a range of phenotypes; two were phenotypically normal, one had a borderline QT interval, and two carriers were diagnosed with classic long QT syndrome. Experimental studies have shown that heterologous expression of this missense change along with KCNE1 generates non-functional channels and causes dominant negative suppression of current in vitro (PMID: 23092362). This sequence change is currently listed in ClinVar as Pathogenic (RCV000057831, Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust); however, the evidence supporting this interpretation has not been provided. This sequence change is not reported in population databases, has been observed in multuple individuals with long QT and has been shown to cause Jervell-Lange Nielsen syndrome in the homozygous state, and there is functional evidence demonstrating that the p.Thr322Met missense change is deleterious. For these reasons, this sequence change has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Medical Research Institute,Tokyo Medical and Dental University, SCV000222064.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot provideddiscoverynot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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