NM_000218.3(KCNQ1):c.785T>C (p.Leu262Pro) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 19, 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:: RCV003647798.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.785T>C (p.Leu262Pro)]

NM_000218.3(KCNQ1):c.785T>C (p.Leu262Pro)

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.785T>C (p.Leu262Pro)

HGVS:

NC_000011.10:g.2572850T>C
NG_008935.1:g.132860T>C
NM_000218.3:c.785T>CMANE SELECT
NM_001406836.1:c.785T>C
NM_001406837.1:c.515T>C
NM_181798.2:c.404T>C
NP_000209.2:p.Leu262Pro
NP_000209.2:p.Leu262Pro
NP_001393765.1:p.Leu262Pro
NP_001393766.1:p.Leu172Pro
NP_861463.1:p.Leu135Pro
NP_861463.1:p.Leu135Pro
LRG_287t1:c.785T>C
LRG_287t2:c.404T>C
LRG_287:g.132860T>C
LRG_287p1:p.Leu262Pro
LRG_287p2:p.Leu135Pro
NC_000011.9:g.2594080T>C
NM_000218.2:c.785T>C
NM_181798.1:c.404T>C
NR_040711.2:n.678T>C

Protein change:

L135P

Links:

dbSNP: rs1564821090

NCBI 1000 Genomes Browser:

rs1564821090

Molecular consequence:

NM_000218.3:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.785T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.515T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.404T>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
SCV004468792	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32383558, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004468792

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 19, 2023)

germline

clinical testing

PubMed (2)
[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

Reclassification of genetic variants in children with long QT syndrome.

Westphal DS, Burkard T, Moscu-Gregor A, Gebauer R, Hessling G, Wolf CM.

Mol Genet Genomic Med. 2020 Sep;8(9):e1300. doi: 10.1002/mgg3.1300. Epub 2020 May 8.

PubMed [citation]

PMID:: 32383558
PMCID:: PMC7506994

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004468792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

ClinVar contains an entry for this variant (Variation ID: 560359). 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.Leu262 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32383558; Invitae). 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 missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 262 of the KCNQ1 protein (p.Leu262Pro).

#	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: Sep 29, 2024

ClinVar

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