NM_000218.3(KCNQ1):c.776G>A (p.Arg259His) AND Long QT syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 11, 2021
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:: RCV000709733.11

Allele description [Variation Report for NM_000218.3(KCNQ1):c.776G>A (p.Arg259His)]

NM_000218.3(KCNQ1):c.776G>A (p.Arg259His)

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.776G>A (p.Arg259His)

Other names:

p.R259H:CGC>CAC

HGVS:

NC_000011.10:g.2572105G>A
NG_008935.1:g.132115G>A
NM_000218.3:c.776G>AMANE SELECT
NM_001406836.1:c.776G>A
NM_001406837.1:c.506G>A
NM_181798.2:c.395G>A
NP_000209.2:p.Arg259His
NP_000209.2:p.Arg259His
NP_001393765.1:p.Arg259His
NP_001393766.1:p.Arg169His
NP_861463.1:p.Arg132His
NP_861463.1:p.Arg132His
LRG_287t1:c.776G>A
LRG_287t2:c.395G>A
LRG_287:g.132115G>A
LRG_287p1:p.Arg259His
LRG_287p2:p.Arg132His
NC_000011.9:g.2593335G>A
NM_000218.2:c.776G>A
NM_181798.1:c.395G>A
NR_040711.2:n.669G>A
P51787:p.Arg259His

Protein change:

R132H

Links:

UniProtKB: P51787#VAR_074964; dbSNP: rs199472720

NCBI 1000 Genomes Browser:

rs199472720

Molecular consequence:

NM_000218.3:c.776G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.776G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.506G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.395G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000839971	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 30, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001440836	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002103007	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000839971

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 30, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001440836

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002103007

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 11, 2021)

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839971.1

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

Description

This c.776G>A (p.Arg259His) variant in the KCNQ1 gene has been reported in multiple LQTS/SQTS patients with significantly higher prevalence than that observed as extremely low in general population according to gnomad database. Arginine at amino acid position 259 is highly conserved during evolution. Arg259Cys, Arg259Gly and Arg259Leu have been reported in multiple LQTS/SQTS patients as deleterious mutations [PMID: 11021476, 15840476, 19716085, 27868350, 21350584]. Multiple in silico predictions suggest this arginine to histidine change is deleterious. Based upon above evidences, this c.776G>A (p.Arg259His) variant in the KCNQ1 gene is 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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440836.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn, SCV002103007.1

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

Description

Incidental finding in clinical exome sequencing. PS1, PS3, PP3

#	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: Apr 20, 2024

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