NM_000218.3(KCNQ1):c.1092C>G (p.Phe364Leu) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 16, 2024
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:: RCV005059587.1

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1092C>G (p.Phe364Leu)]

NM_000218.3(KCNQ1):c.1092C>G (p.Phe364Leu)

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.1092C>G (p.Phe364Leu)

HGVS:

NC_000011.10:g.2585271C>G
NG_008935.1:g.145281C>G
NM_000218.3:c.1092C>GMANE SELECT
NM_001406836.1:c.1032+1726C>G
NM_001406837.1:c.822C>G
NM_001406838.1:c.588+1726C>G
NM_181798.2:c.711C>G
NP_000209.2:p.Phe364Leu
NP_000209.2:p.Phe364Leu
NP_001393766.1:p.Phe274Leu
NP_861463.1:p.Phe237Leu
NP_861463.1:p.Phe237Leu
LRG_287t1:c.1092C>G
LRG_287t2:c.711C>G
LRG_287:g.145281C>G
LRG_287p1:p.Phe364Leu
LRG_287p2:p.Phe237Leu
NC_000011.9:g.2606501C>G
NM_000218.2:c.1092C>G
NM_181798.1:c.711C>G

Protein change:

F237L

Links:

dbSNP: rs2133754700

NCBI 1000 Genomes Browser:

rs2133754700

Molecular consequence:

NM_001406836.1:c.1032+1726C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001406838.1:c.588+1726C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000218.3:c.1092C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.822C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.711C>G - 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
SCV005722690	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 16, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30847666, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005722690

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 16, 2024)

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

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

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, SCV005722690.1

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 364 of the KCNQ1 protein (p.Phe364Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 30847666). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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