NM_000218.3(KCNQ1):c.914G>T (p.Trp305Leu) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002515312.5

Allele description [Variation Report for NM_000218.3(KCNQ1):c.914G>T (p.Trp305Leu)]

NM_000218.3(KCNQ1):c.914G>T (p.Trp305Leu)

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.914G>T (p.Trp305Leu)

Other names:

p.W305L:TGG>TTG

HGVS:

NC_000011.10:g.2572979G>T
NG_008935.1:g.132989G>T
NM_000218.3:c.914G>TMANE SELECT
NM_001406836.1:c.914G>T
NM_001406837.1:c.644G>T
NM_181798.2:c.533G>T
NP_000209.2:p.Trp305Leu
NP_000209.2:p.Trp305Leu
NP_001393765.1:p.Trp305Leu
NP_001393766.1:p.Trp215Leu
NP_861463.1:p.Trp178Leu
NP_861463.1:p.Trp178Leu
LRG_287t1:c.914G>T
LRG_287t2:c.533G>T
LRG_287:g.132989G>T
LRG_287p1:p.Trp305Leu
LRG_287p2:p.Trp178Leu
NC_000011.9:g.2594209G>T
NM_000218.2:c.914G>T
NM_181798.1:c.533G>T
NR_040711.2:n.807G>T

Protein change:

W178L

Links:

dbSNP: rs120074186

NCBI 1000 Genomes Browser:

rs120074186

Molecular consequence:

NM_000218.3:c.914G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.914G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.644G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.533G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV003439751	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 9, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19490272, 19716085, 21451124, 26344792, 28492532
SCV004834315	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26344792, 28532774, 31737537, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003439751

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 9, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004834315

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 2024)

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	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome.

Jons C, Moss AJ, Lopes CM, McNitt S, Zareba W, Goldenberg I, Qi M, Wilde AA, Shimizu W, Kanters JK, Towbin JA, Ackerman MJ, Robinson JL.

J Cardiovasc Electrophysiol. 2009 Aug;20(8):859-65. doi: 10.1111/j.1540-8167.2009.01455.x. Epub 2009 Mar 13.

PubMed [citation]

PMID:: 19490272

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439751.2

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

Description

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. This variant disrupts the p.Trp305 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19490272, 19716085, 21451124, 26344792). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 26344792). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 305 of the KCNQ1 protein (p.Trp305Leu). This variant is present in population databases (rs120074186, gnomAD no frequency). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 26344792). ClinVar contains an entry for this variant (Variation ID: 200824).

#	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

From All of Us Research Program, National Institutes of Health, SCV004834315.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces tryptophan with leucine at codon 305 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved pore region (a.a. 300-320). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant results in significantly decreased peak current densities compared to wild type protein (PMID: 26344792). This variant has been reported in 2 individuals affected with long QT syndrome (PMID: 26344792, 28532774) and 2 individuals with suspected long QT syndrome (PMID: 31737537). This variant was found to partially segregate in a family with long QT syndrome and a syncope phenotype (PMID: 26344792). A different missense variant occurring at the same codon, p.Trp305Ser, is known to be disease-causing (ClinVar variation ID: 3127). This variant has been identified in 1/249180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this p.Trp305Leu variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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