NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val) AND Long QT syndrome 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 18, 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:: RCV002470738.5

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)]

NM_000218.3(KCNQ1):c.1031C>T (p.Ala344Val)

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.1031C>T (p.Ala344Val)

HGVS:

NC_000011.10:g.2583544C>T
NG_008935.1:g.143554C>T
NM_000218.3:c.1031C>TMANE SELECT
NM_001406836.1:c.1031C>T
NM_001406837.1:c.761C>T
NM_001406838.1:c.587C>T
NM_181798.2:c.650C>T
NP_000209.2:p.Ala344Val
NP_000209.2:p.Ala344Val
NP_001393765.1:p.Ala344Val
NP_001393766.1:p.Ala254Val
NP_001393767.1:p.Ala196Val
NP_861463.1:p.Ala217Val
NP_861463.1:p.Ala217Val
LRG_287t1:c.1031C>T
LRG_287t2:c.650C>T
LRG_287:g.143554C>T
LRG_287p1:p.Ala344Val
LRG_287p2:p.Ala217Val
NC_000011.9:g.2604774C>T
NM_000218.2:c.1031C>T
NM_181798.1:c.650C>T
NR_040711.2:n.924C>T
P51787:p.Ala344Val

Protein change:

A196V

Links:

UniProtKB: P51787#VAR_001541; dbSNP: rs199472763

NCBI 1000 Genomes Browser:

rs199472763

Molecular consequence:

NM_000218.3:c.1031C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1031C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.650C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome 1 (LQT1)
Identifiers:: MONDO: MONDO:0100316; MedGen: C4551647; Orphanet: 101016; Orphanet: 768; OMIM: 192500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002766702	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 11, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10508236, 16931984, 19632626, 28944242, 25741868
SCV004024168	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004176139	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Aug 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9386136, 28944242, 31737537, 34505893 Citation Link,
SCV005438539	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Voltage-gated ion channels and hereditary disease.

Lehmann-Horn F, Jurkat-Rott K.

Physiol Rev. 1999 Oct;79(4):1317-72. Review.

PubMed [citation]

PMID:: 10508236

Long QT 1 mutation KCNQ1A344V increases local anesthetic sensitivity of the slowly activating delayed rectifier potassium current.

Siebrands CC, Binder S, Eckhoff U, Schmitt N, Friederich P.

Anesthesiology. 2006 Sep;105(3):511-20.

PubMed [citation]

PMID:: 16931984

See all PubMed Citations (8)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766702.1

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

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID: 19632626). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Long QT syndrome has been associated with variants resulting in both loss-of-function and dominant negative effects (PMID: 19632626). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Long QT syndrome is caused predominantly by heterozygous pathogenic variants (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from an alanine to a valine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (S6 transmembrane helix of the ion transport domain; NCBI, PDB, Decipher, PMID: 10508236). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. At least two different variants in the same codon resulting in a change to a threonine and a glycine have been reported as likely pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been has described as a mild variant and has been previously reported as pathogenic in multiple patients with long QT syndrome (ClinVar, LOVD, PMID: 10508236, PMID: 28944242). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Studies show that this variant induces voltage-dependent inactivation in KCNQ1 channels and shifts the voltage dependence of KCNQ1/KCNE1 complex activation (PMID: 16931984). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes, SCV004024168.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center, SCV004176139.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.1031C>T variant in KCNQ1 has previously been reported in individuals with long QT syndrome (PMID: 9386136, 28944242, 31737537, 34505893) and it has been deposited in ClinVar [ClinVar ID: 52936] as Pathogenic by multiple submitters with affected status provided. The c.1031C>T variant is observed in 1 allele (~0.00017% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.1031C>T variant in KCNQ1 is located in exon 7 of this 16-exon gene and is predicted to replace an evolutionarily conserved alanine amino acid with valine at position 344 (p.(Ala344Val) in the ion transport domain of the encoded protein [UniProt ID: P51787]. Functional studies demonstrated loss of potassium channel function (PMID: 34505893). Different missense variants affecting the same aminoacid residue (p.Ala344) and neighbouring residues within the S segment have been reported in individuals with long QT syndrome in the literature [PMID: 28349240]. Based on available evidence this c.1031C>T p.(Ala344Val) variant identified in KCNQ1 is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV005438539.1

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

#	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: Jun 29, 2025

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Relating variation to medicine