NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 15, 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:: RCV000231075.18

Allele description [Variation Report for NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln)]

NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln)

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.584G>A (p.Arg195Gln)

Other names:

p.R195Q:CGG>CAG

HGVS:

NC_000011.10:g.2570734G>A
NG_008935.1:g.130744G>A
NM_000218.3:c.584G>AMANE SELECT
NM_001406836.1:c.584G>A
NM_001406837.1:c.314G>A
NM_181798.2:c.203G>A
NP_000209.2:p.Arg195Gln
NP_000209.2:p.Arg195Gln
NP_001393765.1:p.Arg195Gln
NP_001393766.1:p.Arg105Gln
NP_861463.1:p.Arg68Gln
NP_861463.1:p.Arg68Gln
LRG_287t1:c.584G>A
LRG_287t2:c.203G>A
LRG_287:g.130744G>A
LRG_287p1:p.Arg195Gln
LRG_287p2:p.Arg68Gln
NC_000011.9:g.2591964G>A
NM_000218.2:c.584G>A
NM_181798.1:c.203G>A
NR_040711.2:n.477G>A

Protein change:

R105Q

Links:

dbSNP: rs138362632

NCBI 1000 Genomes Browser:

rs138362632

Molecular consequence:

NM_000218.3:c.584G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.584G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.203G>A - 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
SCV000283886	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 15, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23861489, 30571187, 28492532
SCV004838764	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19841300, 22949429, 23861489, 25564853, 31696929, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000283886

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 15, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004838764

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 2023)

germline

clinical testing

PubMed (6)
[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	18	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.

Vanoye CG, Desai RR, Fabre KL, Gallagher SL, Potet F, DeKeyser JM, Macaya D, Meiler J, Sanders CR, George AL Jr.

Circ Genom Precis Med. 2018 Nov;11(11):e002345. doi: 10.1161/CIRCGEN.118.002345.

PubMed [citation]

PMID:: 30571187
PMCID:: PMC6309341

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

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000283886.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 195 of the KCNQ1 protein (p.Arg195Gln). This variant is present in population databases (rs138362632, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 67088). 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: 23861489, 30571187). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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, SCV004838764.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	18	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces arginine with glutamine at codon 195 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant reduces the whole-cell current amplitude of the channel (PMID: 23861489) and suppressed the current-enhancing effect of a KCNQ1 activator (PMID: 25564853). This variant has been reported in an individual suspected of having epilepsy (PMID: 31696929) and in two control subjects (PMID: 19841300, 22949429). This variant has also been identified in 11/280490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		18	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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