NM_172107.4(KCNQ2):c.587C>T (p.Ala196Val) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jun 27, 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:: RCV001092637.31

Allele description [Variation Report for NM_172107.4(KCNQ2):c.587C>T (p.Ala196Val)]

NM_172107.4(KCNQ2):c.587C>T (p.Ala196Val)

Gene:

KCNQ2:potassium voltage-gated channel subfamily Q member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.33

Genomic location:

Preferred name:

NM_172107.4(KCNQ2):c.587C>T (p.Ala196Val)

HGVS:

NC_000020.11:g.63444762G>A
NG_009004.2:g.32879C>T
NM_004518.6:c.587C>T
NM_172106.3:c.587C>T
NM_172107.4:c.587C>TMANE SELECT
NM_172108.5:c.587C>T
NM_172109.3:c.587C>T
NP_004509.2:p.Ala196Val
NP_742104.1:p.Ala196Val
NP_742105.1:p.Ala196Val
NP_742106.1:p.Ala196Val
NP_742107.1:p.Ala196Val
NC_000020.10:g.62076115G>A
NM_172107.2:c.587C>T
NM_172107.3:c.587C>T

Protein change:

A196V

Links:

dbSNP: rs118192199

NCBI 1000 Genomes Browser:

rs118192199

Molecular consequence:

NM_004518.6:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172106.3:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172107.4:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172108.5:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172109.3:c.587C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Mild decrease in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0085]
Normal rate of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0011]
Severe depolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0026]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001249242	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2019)	germline	clinical testing	Citation Link,
SCV001740336	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001931984	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002023231	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 7, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004036384	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 27, 2023)	germline	clinical testing	Citation Link,
SCV004225338	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2022)	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	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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 CeGaT Center for Human Genetics Tuebingen, SCV001249242.26

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

#	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		3	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740336.3

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

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001931984.1

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

#	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 Revvity Omics, Revvity, SCV002023231.3

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

#	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 GeneDx, SCV004036384.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on channel function (Soldovieri et al., 2007); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25880994, 24375629, 11690625, 32411386, 34489640, 23360469, 23708187, 16686649, 28717674, 27888506, 17475800)

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004225338.1

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

Description

PP1, PP3, PM2, PM6, PS3, PS4_moderate

#	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		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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