NM_000218.3(KCNQ1):c.783G>C (p.Glu261Asp) AND Long QT syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 17, 2023
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:: RCV001381194.7

Allele description [Variation Report for NM_000218.3(KCNQ1):c.783G>C (p.Glu261Asp)]

NM_000218.3(KCNQ1):c.783G>C (p.Glu261Asp)

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.783G>C (p.Glu261Asp)

HGVS:

NC_000011.10:g.2572848G>C
NG_008935.1:g.132858G>C
NM_000218.3:c.783G>CMANE SELECT
NM_001406836.1:c.783G>C
NM_001406837.1:c.513G>C
NM_181798.2:c.402G>C
NP_000209.2:p.Glu261Asp
NP_000209.2:p.Glu261Asp
NP_001393765.1:p.Glu261Asp
NP_001393766.1:p.Glu171Asp
NP_861463.1:p.Glu134Asp
NP_861463.1:p.Glu134Asp
LRG_287t1:c.783G>C
LRG_287t2:c.402G>C
LRG_287:g.132858G>C
LRG_287p1:p.Glu261Asp
LRG_287p2:p.Glu134Asp
NC_000011.9:g.2594078G>C
NM_000218.2:c.783G>C
NM_181798.1:c.402G>C
NR_040711.2:n.676G>C
P51787:p.Glu261Asp

Protein change:

E134D

Links:

UniProtKB: P51787#VAR_008944; dbSNP: rs199472721

NCBI 1000 Genomes Browser:

rs199472721

Molecular consequence:

NM_000218.3:c.783G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.783G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.513G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.402G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001579495	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 24, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15935335, 10704188, 11530100, 15840476, 18752142, 23631430, 26675252, 28492532
SCV004843088	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 9386136, 10704188, 11140949, 11530100, 15840476, 15935335, 18752142, 19716085, 23631430, 26669661, 26675252, 27041096, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001579495

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 24, 2023)

germline

clinical testing

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

SCV004843088

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (13)
[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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.

Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P.

Circulation. 1997 Nov 4;96(9):2778-81.

PubMed [citation]

PMID:: 9386136

See all PubMed Citations (14)

Details of each submission

From Invitae, SCV001579495.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 11530100, 15935335). 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. ClinVar contains an entry for this variant (Variation ID: 53104). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and clinically confirmed long QT syndrome (PMID: 10704188, 11530100, 15840476, 18752142, 23631430, 26675252; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 261 of the KCNQ1 protein (p.Glu261Asp).

#	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 All of Us Research Program, National Institutes of Health, SCV004843088.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

Description

The c.783G>C (p.Glu261Asp) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in heterozygous status in multiple unrelated individuals (at least 9) with Long QT syndrome (LQTS) (PMID: 15840476, 18752142, 23631430, 26675252) and in one individual affected with Jervell and Lange-Nielsen syndrome (PMID:11140949). This variant has also been observed in compound heterozygous status (with another pathogenic variant p.Glu530*) in two individuals with Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 10704188, 26675252). Expermental studies using Xenopus oocytes showed strong dominant negative effect resulted in pronounced reduction in current amplitude compared to control (PMID: 11530100). When co-expressed with KCNE1 in CHO-K1 and murine myocyte cell line, this variant showed retention of protein to the endoplasmic reticulum and decrease in tail current density (PMID: 15935335). In-silico computational prediction tools suggest that the p.Glu261Aspvariant may have deleterious effect on the protein function (REVEL score: 0.867). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by a submitter in the ClinVar database (ClinVar ID: 53104). Other missense variants substituting the same amino acid (p.Glu261Leu, p.Glu261Gln, p.Glu261Lys) are reported in multiple individuals with LQTS (PMID: 9386136, 19716085, 26669661, 27041096) and classified as likely pathogenic/pathogenic by several submitters in the ClinVar (ClinVar ID: 405253, 67106, 53103). Therefore, the c.783G>C (p.Glu261Asp) variant in the KCNQ1 gene is classified as pathogenic.

#	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: May 7, 2024

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