NM_000218.3(KCNQ1):c.1015T>C (p.Phe339Leu) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 14, 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:: RCV003648885.1

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1015T>C (p.Phe339Leu)]

NM_000218.3(KCNQ1):c.1015T>C (p.Phe339Leu)

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.1015T>C (p.Phe339Leu)

HGVS:

NC_000011.10:g.2583528T>C
NG_008935.1:g.143538T>C
NM_000218.3:c.1015T>CMANE SELECT
NM_001406836.1:c.1015T>C
NM_001406837.1:c.745T>C
NM_001406838.1:c.571T>C
NM_181798.2:c.634T>C
NP_000209.2:p.Phe339Leu
NP_000209.2:p.Phe339Leu
NP_001393765.1:p.Phe339Leu
NP_001393766.1:p.Phe249Leu
NP_001393767.1:p.Phe191Leu
NP_861463.1:p.Phe212Leu
NP_861463.1:p.Phe212Leu
LRG_287t1:c.1015T>C
LRG_287t2:c.634T>C
LRG_287:g.143538T>C
LRG_287p1:p.Phe339Leu
LRG_287p2:p.Phe212Leu
NC_000011.9:g.2604758T>C
NM_000218.2:c.1015T>C
NM_181798.1:c.634T>C
NR_040711.2:n.908T>C

Protein change:

F191L

Molecular consequence:

NM_000218.3:c.1015T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1015T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.745T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.571T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.634T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004557278	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17224687, 19808498, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004557278

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 14, 2023)

germline

clinical testing

PubMed (3)
[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

Whole blood RNA offers a rapid, comprehensive approach to genetic diagnosis of cardiovascular diseases.

Miller TE, You L, Myerburg RJ, Benke PJ, Bishopric NH.

Genet Med. 2007 Jan;9(1):23-33. Erratum in: Genet Med. 2007 Feb;9(2):135.

PubMed [citation]

PMID:: 17224687

Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome.

Yang T, Chung SK, Zhang W, Mullins JG, McCulley CH, Crawford J, MacCormick J, Eddy CA, Shelling AN, French JK, Yang P, Skinner JR, Roden DM, Rees MI.

Circ Arrhythm Electrophysiol. 2009 Aug;2(4):417-26. doi: 10.1161/CIRCEP.109.850149. Epub 2009 May 22.

PubMed [citation]

PMID:: 19808498
PMCID:: PMC2748886

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004557278.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 339 of the KCNQ1 protein (p.Phe339Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. 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%. This variant disrupts the p.Phe339 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17224687, 19808498; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#	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 7, 2024

ClinVar

Relating variation to medicine