NM_000218.3(KCNQ1):c.911G>T (p.Trp304Leu) AND Long QT syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 24, 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:: RCV003842940.2

Allele description [Variation Report for NM_000218.3(KCNQ1):c.911G>T (p.Trp304Leu)]

NM_000218.3(KCNQ1):c.911G>T (p.Trp304Leu)

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.911G>T (p.Trp304Leu)

HGVS:

NC_000011.10:g.2572976G>T
NG_008935.1:g.132986G>T
NM_000218.3:c.911G>TMANE SELECT
NM_001406836.1:c.911G>T
NM_001406837.1:c.641G>T
NM_001406838.1:c.478-10459G>T
NM_181798.2:c.530G>T
NP_000209.2:p.Trp304Leu
NP_000209.2:p.Trp304Leu
NP_001393765.1:p.Trp304Leu
NP_001393766.1:p.Trp214Leu
NP_861463.1:p.Trp177Leu
NP_861463.1:p.Trp177Leu
LRG_287t1:c.911G>T
LRG_287t2:c.530G>T
LRG_287:g.132986G>T
LRG_287p1:p.Trp304Leu
LRG_287p2:p.Trp177Leu
NC_000011.9:g.2594206G>T
NM_000218.2:c.911G>T
NM_181798.1:c.530G>T
NR_040711.2:n.804G>T

Protein change:

W177L

Molecular consequence:

NM_001406838.1:c.478-10459G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000218.3:c.911G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.911G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.641G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.530G>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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protein MAL2 [Homo sapiens]
protein MAL2 [Homo sapiens]
gi|16418397|ref|NP_443118.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004640746	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22949429, 32470535, 19017345, 32383558, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004640746

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 24, 2023)

germline

clinical testing

PubMed (5)
[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

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]

PMID:: 22949429
PMCID:: PMC3705705

Genetic homozygosity in a diverse population: An experience of long QT syndrome.

Mahdieh N, Khorgami M, Soveizi M, Seyed Aliakbar S, Dalili M, Rabbani B.

Int J Cardiol. 2020 Oct 1;316:117-124. doi: 10.1016/j.ijcard.2020.05.056. Epub 2020 May 26.

PubMed [citation]

PMID:: 32470535

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004640746.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 304 of the KCNQ1 protein (p.Trp304Leu). 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.Trp304 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22949429, 32470535), which suggests that this may be a clinically significant amino acid residue. 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 individuals with long QT Syndrome (PMID: 19017345, 32383558). This variant is not present in population databases (gnomAD no frequency).

#	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

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