NM_000748.3(CHRNB2):c.859G>T (p.Val287Leu) AND Autosomal dominant nocturnal frontal lobe epilepsy 3

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 10, 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:: RCV002286498.2

Allele description [Variation Report for NM_000748.3(CHRNB2):c.859G>T (p.Val287Leu)]

NM_000748.3(CHRNB2):c.859G>T (p.Val287Leu)

Gene:

CHRNB2:cholinergic receptor nicotinic beta 2 subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

NM_000748.3(CHRNB2):c.859G>T (p.Val287Leu)

HGVS:

NC_000001.11:g.154571682G>T
NG_008027.1:g.8902G>T
NM_000748.3:c.859G>TMANE SELECT
NP_000739.1:p.Val287Leu
NC_000001.10:g.154544158G>T
NM_000748.2:c.859G>T
P17787:p.Val287Leu

Protein change:

V287L

Links:

UniProtKB: P17787#VAR_012714

Molecular consequence:

NM_000748.3:c.859G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal dominant nocturnal frontal lobe epilepsy 3
Synonyms:: Epilepsy, nocturnal frontal lobe, type 3
Identifiers:: MONDO: MONDO:0011545; MedGen: C1854335; Orphanet: 98784; OMIM: 605375

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Mndal myeloid nuclear differentiation antigen like [Mus musculus]
Mndal myeloid nuclear differentiation antigen like [Mus musculus]
Gene ID:100040462

Gene
100040462[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002576471	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 16, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003934659	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 10, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11062464, 22897520, 27336596, 19059498, 19237585, 22036597 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002576471

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 16, 2022)

unknown

clinical testing

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

SCV003934659

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 10, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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

The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy.

De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, Ballabio A, Wanke E, Casari G.

Nat Genet. 2000 Nov;26(3):275-6.

PubMed [citation]

PMID:: 11062464

See all PubMed Citations (7)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002576471.1

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

Description

_x000D_ Criteria applied: PS1, PM1, PM5, PM2_SUP

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934659.1

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

Description

Variant summary: CHRNB2 c.859G>T (p.Val287Leu) results in a conservative amino acid change located in the Neurotransmitter-gated ion-channel transmembrane domain (IPR006029) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251228 control chromosomes (gnomAD). c.859G>T has been reported in the literature in multiple individuals affected with autosomal dominant nocturnal frontal lobe epilepsy (DeFusco_2000, Picard_2008, Labate_2012) and this variant co-segregated with disease (DeFusco_2000, Labate_2012). These data indicate that the variant is very likely to be associated with disease. At least two publication report this variant alters the subunit composition and sensitivity of 42 nAChRs, and increases 542 surface expression (DeFusco_2000, Nichols_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22897520, 19059498, 19237585, 22036597, 27336596). Two ClinVar submitters (evaluation after 2014) cite this variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Sep 29, 2024

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