NM_000747.3(CHRNB1):c.865G>A (p.Val289Met) AND Congenital myasthenic syndrome 2A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 9, 2022
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:: RCV000020040.40

Allele description [Variation Report for NM_000747.3(CHRNB1):c.865G>A (p.Val289Met)]

NM_000747.3(CHRNB1):c.865G>A (p.Val289Met)

Gene:

CHRNB1:cholinergic receptor nicotinic beta 1 subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000747.3(CHRNB1):c.865G>A (p.Val289Met)

Other names:

V266M

HGVS:

NC_000017.11:g.7454341G>A
NG_008026.1:g.14255G>A
NM_000747.3:c.865G>AMANE SELECT
NP_000738.2:p.Val289Met
NC_000017.10:g.7357660G>A
NM_000747.2:c.865G>A
P11230:p.Val289Met

Protein change:

V289M; VAL266MET

Links:

UniProtKB: P11230#VAR_000288; OMIM: 100710.0001; dbSNP: rs137852810

NCBI 1000 Genomes Browser:

rs137852810

Molecular consequence:

NM_000747.3:c.865G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital myasthenic syndrome 2A
Synonyms:: Myasthenic syndrome, congenital, 2a, slow-channel
Identifiers:: MONDO: MONDO:0014581; MedGen: C4225374; Orphanet: 590; OMIM: 616313

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040338	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 1996)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000656611	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 9, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8872460, 20562457, 27391121, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000040338

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 1996)

germline

literature only

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

SCV000656611

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 9, 2022)

germline

clinical testing

PubMed (4)
[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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome.

Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt JN 2nd, Hutchinson DO, Brengman JM, Bren N, Sieb JP, Sine SM.

Hum Mol Genet. 1996 Sep;5(9):1217-27.

PubMed [citation]

PMID:: 8872460

Molecular characterisation of congenital myasthenic syndromes in Southern Brazil.

Mihaylova V, Scola RH, Gervini B, Lorenzoni PJ, Kay CK, Werneck LC, Stucka R, Guergueltcheva V, von der Hagen M, Huebner A, Abicht A, Müller JS, Lochmüller H.

J Neurol Neurosurg Psychiatry. 2010 Sep;81(9):973-7. doi: 10.1136/jnnp.2009.177816. Epub 2010 Jun 20.

PubMed [citation]

PMID:: 20562457

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000040338.3

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

Description

In a 19-year-old female with slow-channel congenital myasthenic syndrome-2A (CMS2A; 616313), Engel et al. (1996) identified a heterozygous 796G-A transition in exon 8 of the CHRNB1 gene, resulting in a val266-to-met (V266M) substitution in a conserved residue in the M2 transmembrane domain of the AChR-beta subunit. Functional expression studies showed that the V266M mutation slowed the rate of AChR channel closure and increased the apparent affinity for ACh. The mutation also caused pathologic channel openings even in the absence of ACh, resulting in a leaky channel. Cationic overload of the postsynaptic region caused an endplate myopathy.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000656611.7

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNB1 function (PMID: 8872460). 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 expected to disrupt CHRNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 18372). This missense change has been observed in individuals with autosomal dominant slow-channel congenital myasthenic syndrome (PMID: 8872460, 20562457, 27391121). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 289 of the CHRNB1 protein (p.Val289Met).

#	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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