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NM_000218.3(KCNQ1):c.728G>T (p.Arg243Leu) AND Long QT syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 4, 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:
RCV003648949.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.728G>T (p.Arg243Leu)]

NM_000218.3(KCNQ1):c.728G>T (p.Arg243Leu)

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.728G>T (p.Arg243Leu)
HGVS:
  • NC_000011.10:g.2572057G>T
  • NG_008935.1:g.132067G>T
  • NM_000218.3:c.728G>TMANE SELECT
  • NM_001406836.1:c.728G>T
  • NM_001406837.1:c.458G>T
  • NM_001406838.1:c.478-11378G>T
  • NM_181798.2:c.347G>T
  • NP_000209.2:p.Arg243Leu
  • NP_000209.2:p.Arg243Leu
  • NP_001393765.1:p.Arg243Leu
  • NP_001393766.1:p.Arg153Leu
  • NP_861463.1:p.Arg116Leu
  • NP_861463.1:p.Arg116Leu
  • LRG_287t1:c.728G>T
  • LRG_287t2:c.347G>T
  • LRG_287:g.132067G>T
  • LRG_287p1:p.Arg243Leu
  • LRG_287p2:p.Arg116Leu
  • NC_000011.9:g.2593287G>T
  • NM_000218.2:c.728G>T
  • NM_181798.1:c.347G>T
  • NR_040711.2:n.621G>T
Protein change:
R116L
Molecular consequence:
  • NM_001406838.1:c.478-11378G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000218.3:c.728G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406836.1:c.728G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406837.1:c.458G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181798.2:c.347G>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004532854Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 4, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk.

Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, Drici MD, Guicheney P, Barhanin J.

Cardiovasc Res. 2000 Mar;45(4):971-80.

PubMed [citation]
PMID:
10728423

Use of the newborn screening card to define cause of death in a 12-year-old diagnosed with epilepsy.

Skinner JR, Chong B, Fawkner M, Webster DR, Hegde M.

J Paediatr Child Health. 2004 Nov;40(11):651-3.

PubMed [citation]
PMID:
15469540
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004532854.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg243 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10728423, 15469540, 20167303, 23400408, 26022593). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 243 of the KCNQ1 protein (p.Arg243Leu).

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

Last Updated: Sep 29, 2024