NM_000748.3(CHRNB2):c.923T>C (p.Val308Ala) AND Autosomal dominant nocturnal frontal lobe epilepsy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001382226.14

Allele description [Variation Report for NM_000748.3(CHRNB2):c.923T>C (p.Val308Ala)]

NM_000748.3(CHRNB2):c.923T>C (p.Val308Ala)

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.923T>C (p.Val308Ala)

HGVS:

NC_000001.11:g.154571746T>C
NG_008027.1:g.8966T>C
NM_000748.3:c.923T>CMANE SELECT
NP_000739.1:p.Val308Ala
NC_000001.10:g.154544222T>C
NM_000748.2:c.923T>C

Protein change:

V308A

Links:

dbSNP: rs281865070

NCBI 1000 Genomes Browser:

rs281865070

Molecular consequence:

NM_000748.3:c.923T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
Identifiers:: MONDO: MONDO:0020300; MedGen: C3696898

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001580898	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18456869, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001580898

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 8, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore.

Hoda JC, Gu W, Friedli M, Phillips HA, Bertrand S, Antonarakis SE, Goudie D, Roberts R, Scheffer IE, Marini C, Patel J, Berkovic SF, Mulley JC, Steinlein OK, Bertrand D.

Mol Pharmacol. 2008 Aug;74(2):379-91. doi: 10.1124/mol.107.044545. Epub 2008 May 2.

PubMed [citation]

PMID:: 18456869

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001580898.4

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

Description

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 308 of the CHRNB2 protein (p.Val308Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of nocturnal frontal lobe epilepsy (PMID: 18456869). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41035). 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 not expected to disrupt CHRNB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CHRNB2 function (PMID: 18456869). 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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