NM_139343.3(BIN1):c.433C>T (p.Arg145Cys) AND Myopathy, centronuclear, 2

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 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:: RCV000754844.9

Allele description [Variation Report for NM_139343.3(BIN1):c.433C>T (p.Arg145Cys)]

NM_139343.3(BIN1):c.433C>T (p.Arg145Cys)

Gene:

BIN1:bridging integrator 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q14.3

Genomic location:

Preferred name:

NM_139343.3(BIN1):c.433C>T (p.Arg145Cys)

HGVS:

NC_000002.12:g.127069010G>A
NG_012042.1:g.43279C>T
NM_001320632.2:c.433C>T
NM_001320633.2:c.433C>T
NM_001320634.1:c.361C>T
NM_001320640.2:c.433C>T
NM_001320641.2:c.433C>T
NM_001320642.1:c.352C>T
NM_004305.4:c.433C>T
NM_139343.3:c.433C>TMANE SELECT
NM_139344.3:c.433C>T
NM_139345.3:c.433C>T
NM_139346.3:c.433C>T
NM_139347.3:c.433C>T
NM_139348.3:c.433C>T
NM_139349.3:c.433C>T
NM_139350.3:c.433C>T
NM_139351.3:c.433C>T
NP_001307561.1:p.Arg145Cys
NP_001307562.1:p.Arg145Cys
NP_001307563.1:p.Arg121Cys
NP_001307569.1:p.Arg145Cys
NP_001307570.1:p.Arg145Cys
NP_001307571.1:p.Arg118Cys
NP_004296.1:p.Arg145Cys
NP_647593.1:p.Arg145Cys
NP_647594.1:p.Arg145Cys
NP_647595.1:p.Arg145Cys
NP_647596.1:p.Arg145Cys
NP_647597.1:p.Arg145Cys
NP_647598.1:p.Arg145Cys
NP_647599.1:p.Arg145Cys
NP_647600.1:p.Arg145Cys
NP_647601.1:p.Arg145Cys
LRG_873t1:c.433C>T
LRG_873:g.43279C>T
LRG_873p1:p.Arg145Cys
NC_000002.11:g.127826586G>A
NM_004305.3:c.433C>T

Protein change:

R118C; ARG145CYS

Links:

OMIM: 601248.0006; dbSNP: rs1249621033

NCBI 1000 Genomes Browser:

rs1249621033

Molecular consequence:

NM_001320632.2:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320633.2:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320634.1:c.361C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320640.2:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320641.2:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320642.1:c.352C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004305.4:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139343.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139344.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139345.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139346.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139347.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139348.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139349.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139350.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139351.3:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myopathy, centronuclear, 2 (CNM2)
Synonyms:: MYOTUBULAR MYOPATHY, AUTOSOMAL RECESSIVE
Identifiers:: MONDO: MONDO:0009709; MedGen: C0410204; Orphanet: 169186; OMIM: 255200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000882724	OMIM	no assertion criteria provided	Pathogenic (Feb 8, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000930063	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 8, 2019)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 29950440, 25741868
SCV002252306	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29950440, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000882724

OMIM

no assertion criteria provided

Pathogenic
(Feb 8, 2019)

germline

literature only

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

SCV000930063

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 8, 2019)

unknown

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV002252306

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	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

A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine.

Cabrera-Serrano M, Mavillard F, Biancalana V, Rivas E, Morar B, Hernández-Laín A, Olive M, Muelas N, Khan E, Carvajal A, Quiroga P, Diaz-Manera J, Davis M, Ávila R, Domínguez C, Romero NB, Vílchez JJ, Comas D, Laing NG, Laporte J, Kalaydjieva L, Paradas C.

Neurology. 2018 Jul 24;91(4):e339-e348. doi: 10.1212/WNL.0000000000005862. Epub 2018 Jun 27.

PubMed [citation]

PMID:: 29950440
PMCID:: PMC6070382

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000882724.1

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

Description

For discussion of the c.433C-T transition (c.433C-T, NM_139343) in the BIN1 gene, resulting in an arg145-to-cys (R145C) substitution, that was found in compound heterozygous state in Spanish Roma patients with centronuclear myopathy (CNM2; 255200) by Cabrera-Serrano et al. (2018), see 601248.0005.

#	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 SIB Swiss Institute of Bioinformatics, SCV000930063.1

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

Description

This variant is interpreted as a Likely pathogenic for Myopathy, centronuclear, 2 autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 : Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 : Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PP1 : Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:29950440). PM3 : For recessive disorders, detected in trans with a pathogenic variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002252306.4

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 145 of the BIN1 protein (p.Arg145Cys). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 BIN1 protein function. ClinVar contains an entry for this variant (Variation ID: 617682). This missense change has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 29950440). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.0009%).

#	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: Apr 7, 2025

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