NM_000218.3(KCNQ1):c.692G>A (p.Arg231His) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 27, 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:: RCV000046107.14

Allele description [Variation Report for NM_000218.3(KCNQ1):c.692G>A (p.Arg231His)]

NM_000218.3(KCNQ1):c.692G>A (p.Arg231His)

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.692G>A (p.Arg231His)

Other names:

p.R231H:CGC>CAC

HGVS:

NC_000011.10:g.2572021G>A
NG_008935.1:g.132031G>A
NM_000218.3:c.692G>AMANE SELECT
NM_001406836.1:c.692G>A
NM_001406837.1:c.422G>A
NM_181798.2:c.311G>A
NP_000209.2:p.Arg231His
NP_000209.2:p.Arg231His
NP_001393765.1:p.Arg231His
NP_001393766.1:p.Arg141His
NP_861463.1:p.Arg104His
NP_861463.1:p.Arg104His
LRG_287t1:c.692G>A
LRG_287t2:c.311G>A
LRG_287:g.132031G>A
LRG_287p1:p.Arg231His
LRG_287p2:p.Arg104His
NC_000011.9:g.2593251G>A
NM_000218.2:c.692G>A
NM_181798.1:c.311G>A
NR_040711.2:n.585G>A
P51787:p.Arg231His

Protein change:

R104H; ARG231HIS

Links:

UniProtKB: P51787#VAR_074957; OMIM: 607542.0043; dbSNP: rs199472709

NCBI 1000 Genomes Browser:

rs199472709

Molecular consequence:

NM_000218.3:c.692G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.692G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.422G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.311G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000074120	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16414944, 24861447, 23350853, 15176425, 20850564, 22509038, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000074120

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 2023)

germline

clinical testing

PubMed (7)
[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

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, Bottelli G, Cerrone M, Leonardi S.

JAMA. 2005 Dec 21;294(23):2975-80.

PubMed [citation]

PMID:: 16414944

Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome.

Laksman ZW, Gula LJ, Saklani P, Cassagneau R, Steinberg C, Conacher S, Yee R, Skanes A, Leong-Sit P, Manlucu J, Klein GJ, Krahn AD.

Heart Rhythm. 2014 Sep;11(9):1632-8. doi: 10.1016/j.hrthm.2014.05.027. Epub 2014 May 24.

PubMed [citation]

PMID:: 24861447

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000074120.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 231 of the KCNQ1 protein (p.Arg231His). This variant is present in population databases (rs199472709, gnomAD 0.3%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16414944, 23350853, 24861447). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53087). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23350853). This variant disrupts the p.Arg231 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15176425, 20850564, 22509038). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Mar 16, 2024

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