NM_172107.4(KCNQ2):c.601C>T (p.Arg201Cys) AND Developmental and epileptic encephalopathy, 7

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Apr 20, 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:: RCV000203591.13

Allele description [Variation Report for NM_172107.4(KCNQ2):c.601C>T (p.Arg201Cys)]

NM_172107.4(KCNQ2):c.601C>T (p.Arg201Cys)

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.601C>T (p.Arg201Cys)

Other names:

p.R201C:CGC>TGC; NM_004518.4(KCNQ2):c.601C>T(p.Arg201Cys); NM_172106.1(KCNQ2):c.601C>T(p.Arg201Cys); NM_172107.2(KCNQ2):c.601C>T(p.Arg201Cys); NM_172108.3(KCNQ2):c.601C>T(p.Arg201Cys); NM_172109.1(KCNQ2):c.601C>T(p.Arg201Cys)

HGVS:

NC_000020.11:g.63444748G>A
NG_009004.2:g.32893C>T
NM_004518.6:c.601C>T
NM_172106.3:c.601C>T
NM_172107.4:c.601C>TMANE SELECT
NM_172108.5:c.601C>T
NM_172109.3:c.601C>T
NP_004509.2:p.Arg201Cys
NP_742104.1:p.Arg201Cys
NP_742105.1:p.Arg201Cys
NP_742106.1:p.Arg201Cys
NP_742107.1:p.Arg201Cys
NC_000020.10:g.62076101G>A
NM_172107.2:c.601C>T
NM_172107.3:c.601C>T

Protein change:

R201C

Links:

dbSNP: rs796052623

NCBI 1000 Genomes Browser:

rs796052623

Molecular consequence:

NM_004518.6:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172106.3:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172107.4:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172108.5:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172109.3:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Increase in peak current [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0092]
Severe hyperpolarizing shift of voltage dependence of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0031]
Severe slowing of activation [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0015]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 7 (DEE7)
Synonyms:: Early infantile epileptic encephalopathy 7; KCNQ2-Related Neonatal Epileptic Encephalopathy
Identifiers:: MONDO: MONDO:0013387; MedGen: C3150986; Orphanet: 439218; OMIM: 613720

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000258970	NeuroMeGen, Hospital Clinico Santiago de Compostela	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25740509, 25741868
SCV000484565	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 24107868, 25740509
SCV000803440	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2018)	unknown	curation	PubMed (6) [See all records that cite these PMIDs] 25740509, 26993267, 28133863, 24107868, 28687180, 25741868
SCV002318583	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27535030, 24107868, 23708187, 25741868
SCV002564399	Center of Excellence for Medical Genomics, Chulalongkorn University	no assertion criteria provided	Pathogenic (Aug 19, 2022)	de novo	research
SCV003841226	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003919004	Duke University Health System Sequencing Clinic, Duke University Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2023)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV004047256	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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	1	not provided	not provided	1	not provided	clinical testing, literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits.

Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Migliore M, Migliore R, Taglialatela M.

J Neurosci. 2015 Mar 4;35(9):3782-93. doi: 10.1523/JNEUROSCI.4423-14.2015.

PubMed [citation]

PMID:: 25740509
PMCID:: PMC6605567

Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.

Trump N, McTague A, Brittain H, Papandreou A, Meyer E, Ngoh A, Palmer R, Morrogh D, Boustred C, Hurst JA, Jenkins L, Kurian MA, Scott RH.

J Med Genet. 2016 May;53(5):310-7. doi: 10.1136/jmedgenet-2015-103263. Epub 2016 Mar 18.

PubMed [citation]

PMID:: 26993267
PMCID:: PMC4862068

See all PubMed Citations (8)

Details of each submission

From NeuroMeGen, Hospital Clinico Santiago de Compostela, SCV000258970.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

From GeneReviews, SCV000484565.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

EE (epileptic encephalopathy)

#	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 SIB Swiss Institute of Bioinformatics, SCV000803440.1

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

Description

This variant is interpreted as a Pathogenic, for Epileptic encephalopathy, early infantile, 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Loss of voltage-dependent channel gating and increased channel activation, gain-of-function mutation (PMID:25740509). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:26993267,28133863,24107868,28687180). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28687180).

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

From 3billion, SCV002318583.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000205869, PMID:24107868). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27535030). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000369753, PMID:23708187). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.931>=0.6, 3CNET: 0.997>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Center of Excellence for Medical Genomics, Chulalongkorn University, SCV002564399.1

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

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

From Baylor Genetics, SCV003841226.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Duke University Health System Sequencing Clinic, Duke University Health System, SCV003919004.1

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047256.1

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

Description

The missense variant c.601C>T (p.Arg201Cys) in the KCNQ2 gene has been reported in heterozygous state in an individual affected with early onset epileptic encephalopathy (Hortigüela M. et al., 2017). Experimental studies have shown that this missense change stabilized the activated state of the channel, thereby producing gain-of function (Miceli F. et al., 2015). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes databases. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Uncertain Significance. The amino acid Arginine at position 201 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as 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

Last Updated: Apr 15, 2024

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