NM_000218.3(KCNQ1):c.973G>C (p.Gly325Arg) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 13, 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:: RCV000817822.8

Allele description [Variation Report for NM_000218.3(KCNQ1):c.973G>C (p.Gly325Arg)]

NM_000218.3(KCNQ1):c.973G>C (p.Gly325Arg)

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.973G>C (p.Gly325Arg)

HGVS:

NC_000011.10:g.2583486G>C
NG_008935.1:g.143496G>C
NM_000218.3:c.973G>CMANE SELECT
NM_001406836.1:c.973G>C
NM_001406837.1:c.703G>C
NM_001406838.1:c.529G>C
NM_181798.2:c.592G>C
NP_000209.2:p.Gly325Arg
NP_000209.2:p.Gly325Arg
NP_001393765.1:p.Gly325Arg
NP_001393766.1:p.Gly235Arg
NP_001393767.1:p.Gly177Arg
NP_861463.1:p.Gly198Arg
NP_861463.1:p.Gly198Arg
LRG_287t1:c.973G>C
LRG_287t2:c.592G>C
LRG_287:g.143496G>C
LRG_287p1:p.Gly325Arg
LRG_287p2:p.Gly198Arg
NC_000011.9:g.2604716G>C
NM_000218.2:c.973G>C
NM_181798.1:c.592G>C
NR_040711.2:n.866G>C

Protein change:

G177R

Links:

dbSNP: rs199472756

NCBI 1000 Genomes Browser:

rs199472756

Molecular consequence:

NM_000218.3:c.973G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.973G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.703G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.529G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.592G>C - 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
SCV000958405	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 13, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10973849, 15234419, 21118729, 22456477, 23000022, 23092362, 23158531, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000958405

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 13, 2023)

germline

clinical testing

PubMed (8)
[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

Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT.

Circulation. 2000 Sep 5;102(10):1178-85.

PubMed [citation]

PMID:: 10973849

Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan.

Shimizu W, Horie M, Ohno S, Takenaka K, Yamaguchi M, Shimizu M, Washizuka T, Aizawa Y, Nakamura K, Ohe T, Aiba T, Miyamoto Y, Yoshimasa Y, Towbin JA, Priori SG, Kamakura S.

J Am Coll Cardiol. 2004 Jul 7;44(1):117-25.

PubMed [citation]

PMID:: 15234419

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958405.4

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

Description

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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23000022, 23092362). ClinVar contains an entry for this variant (Variation ID: 660595). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10973849, 15234419, 21118729, 22456477, 23000022, 23092362, 23158531). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the KCNQ1 protein (p.Gly325Arg).

#	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: Sep 29, 2024

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