NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln) AND KCNQ1-related disorder

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 1, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV003335087.3

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]

Condition(s)

Name:: KCNQ1-related disorder
Synonyms:: KCNQ1-Related Disorders; KCNQ1-related condition
Identifiers:: MedGen: CN239322

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004046080	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004113231	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 1, 2023)	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

SCV004046080

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

SCV004113231

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 1, 2023)

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	germline	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 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046080.1

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

Description

This variant is also known as c.203G>A (p.Arg68Gln) in an alternate KCNQ1 transcript (NM_181798.1). This variant has been previously reported in individuals with Long QT syndrome (LQTS; PMID: 29197658). The c.584G>A (p.Arg195Gln) variant is located in a mutational hotspot for pathogenic variations associated with LQTS (PMID: 29851656). This change is predicted by multiple in silico tools to have a deleterious effect on protein function, and functional studies have shown that it alters the protein's voltage-gating activity (PMID: 23861489). Pathogenic missense variants are an established mechanism of disease for KCNQ1-related disorders (PMID: 29532034, 30571187, 29851656, 29197658, 19632626), including a missense variant at the same amino acid residue reported in LQTS (Arg159Pro; PMID: 29532034, 30571187). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (11/280490) and thus is presumed to be rare. Based on the available evidence, the c.584G>A (p.Arg195Gln) variant is classified as Likely Pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV004113231.1

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

Description

The KCNQ1 c.584G>A variant is predicted to result in the amino acid substitution p.Arg195Gln. This variant has been previously observed in a cohort of individuals with cardiomyopathy (reported as “benign polymorphism/score 2” in Supplementary table 3, Ng et al. 2013. PubMed ID: 23861362), and a healthy control from a cohort of individuals participating in a case-control study of long QT syndrome (Table S1, Kapa et al. 2009. PubMed ID: 19841300). In vitro functional studies and/or in silico predicting models report conflicting interpretations regarding this variant’s pathogenicity (Kernik et al. 2020. PubMed ID: 32797034; Vanoye et al. 2018. PubMed ID: 30571187; Zaydman et al. 2013. PubMed ID: 23861489). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2591964-G-A). Based on gnomAD frequency data, a recent study considered this variant as statistically too common to be a LQT1-causative variant and recommended downgrading it (Clemens et al. 2018. PubMed ID: 29197658). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#	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: Oct 8, 2024

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