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

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 22, 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:: RCV001384422.9

Allele description

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 (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Melanotaenia praecox isolate Mprae.Pagai.3 cytochrome b (Cytb) gene, complete cd...
Melanotaenia praecox isolate Mprae.Pagai.3 cytochrome b (Cytb) gene, complete cds; mitochondrial
gi|827515613|gb|KP345873.1|

Nucleotide
Melanotaenia praecox isolate Mprae.Kali.3 ribosomal protein S7 (S7) gene, exons ...
Melanotaenia praecox isolate Mprae.Kali.3 ribosomal protein S7 (S7) gene, exons 1 through 3 and partial cds
gi|827515583|gb|KP345858.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001583910	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9386136, 16922724, 17088455, 17470695, 19490272, 24217263, 16931984, 28492532
SCV004022055	Dept of Medical Biology, Uskudar University	criteria provided, single submitter (Dept of Medical Biology Variant Classification)	Pathogenic (Jan 8, 2024)	paternal	research	Citation Link,
SCV004829732	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9386136, 9570196, 15466642, 15840476, 16931984, 17470695, 19716085, 32893267, 36102233, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001583910

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004022055

Dept of Medical Biology, Uskudar University

criteria provided, single submitter

(Dept of Medical Biology Variant Classification)

Pathogenic
(Jan 8, 2024)

paternal

research

Citation Link,

SCV004829732

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 16, 2023)

germline

clinical testing

PubMed (10)
[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	1	not provided	not provided	108544	not provided	clinical testing
Turkish	paternal	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.

Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, Fayol L, Gonzàlez Armengod C, Oddou B, Chanavat V, Froidefond E, Perraudin R, Rousson R, Rodriguez-Lafrasse C.

Clin Genet. 2006 Sep;70(3):214-27.

PubMed [citation]

PMID:: 16922724

Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications.

Tan HL, Bardai A, Shimizu W, Moss AJ, Schulze-Bahr E, Noda T, Wilde AA.

Circulation. 2006 Nov 14;114(20):2096-103. Epub 2006 Nov 6.

PubMed [citation]

PMID:: 17088455

See all PubMed Citations (15)

Details of each submission

From Invitae, SCV001583910.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 344 of the KCNQ1 protein (p.Ala344Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9386136, 16922724, 17088455, 17470695, 19490272, 24217263). ClinVar contains an entry for this variant (Variation ID: 52936). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 16931984). For these reasons, this variant has been classified as 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

From Dept of Medical Biology, Uskudar University, SCV004022055.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Turkish	1	not provided	not provided	research	not provided

Description

Criteria: PS4_Strong, PS3_Moderate, PM1, PM2, PP3

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

From All of Us Research Program, National Institutes of Health, SCV004829732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

This variant has been reported in multiple individuals with long QT syndrome (PMID: 9386136, 15466642, 15840476, 19716085, 9570196, 17470695, 32893267, 36102233). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 19716085). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 16931984).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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