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NM_139343.3(BIN1):c.700C>T (p.Arg234Cys) AND Myopathy, centronuclear, 2

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Dec 15, 2021
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:
RCV000754843.6

Allele description [Variation Report for NM_139343.3(BIN1):c.700C>T (p.Arg234Cys)]

NM_139343.3(BIN1):c.700C>T (p.Arg234Cys)

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.700C>T (p.Arg234Cys)
HGVS:
  • NC_000002.12:g.127063645G>A
  • NG_012042.1:g.48644C>T
  • NM_001320632.2:c.607C>T
  • NM_001320633.2:c.700C>T
  • NM_001320634.1:c.535C>T
  • NM_001320640.2:c.700C>T
  • NM_001320641.2:c.607C>T
  • NM_001320642.1:c.619C>T
  • NM_004305.4:c.607C>T
  • NM_139343.3:c.700C>TMANE SELECT
  • NM_139344.3:c.700C>T
  • NM_139345.3:c.700C>T
  • NM_139346.3:c.607C>T
  • NM_139347.3:c.607C>T
  • NM_139348.3:c.607C>T
  • NM_139349.3:c.607C>T
  • NM_139350.3:c.607C>T
  • NM_139351.3:c.607C>T
  • NP_001307561.1:p.Arg203Cys
  • NP_001307562.1:p.Arg234Cys
  • NP_001307563.1:p.Arg179Cys
  • NP_001307569.1:p.Arg234Cys
  • NP_001307570.1:p.Arg203Cys
  • NP_001307571.1:p.Arg207Cys
  • NP_004296.1:p.Arg203Cys
  • NP_647593.1:p.Arg234Cys
  • NP_647594.1:p.Arg234Cys
  • NP_647595.1:p.Arg234Cys
  • NP_647596.1:p.Arg203Cys
  • NP_647597.1:p.Arg203Cys
  • NP_647598.1:p.Arg203Cys
  • NP_647599.1:p.Arg203Cys
  • NP_647600.1:p.Arg203Cys
  • NP_647601.1:p.Arg203Cys
  • LRG_873t1:c.700C>T
  • LRG_873:g.48644C>T
  • LRG_873p1:p.Arg234Cys
  • NC_000002.11:g.127821221G>A
  • NM_004305.3:c.607C>T
Protein change:
R179C; ARG234CYS
Links:
OMIM: 601248.0005; dbSNP: rs777176261
NCBI 1000 Genomes Browser:
rs777176261
Molecular consequence:
  • NM_001320632.2:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320633.2:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320634.1:c.535C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320640.2:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320641.2:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320642.1:c.619C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004305.4:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139343.3:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139344.3:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139345.3:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139346.3:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139347.3:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139348.3:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139349.3:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139350.3:c.607C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139351.3:c.607C>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000882723OMIM
no assertion criteria provided
Pathogenic
(Feb 8, 2019)
germlineliterature only

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

SCV000930062SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 8, 2019)
unknowncuration

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

SCV003786394Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 15, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedcuration

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, SCV000882723.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 18 patients diagnosed with centronuclear myopathy (CNM2; 255200), Cabrera-Serrano et al. (2018) identified biallelic mutations in the BIN1 gene: 16 were homozygous for a c.700C-T transition in the BIN1 gene, resulting in an arg234-to-cys (R234C) mutation, and 2 were compound heterozygous for R234C and a c.433C-T transition, resulting in an arg145-to-cys (R145C; 601248.0006) substitution. Both mutations occurred at highly conserved residues within the BAR domain and had a low carrier frequency in the gnomAD database (0.0008% for R234C and 0.0004% for R145C). All 15 of the known Spanish Roma patients had the R234C mutation, which was found by haplotype analysis to be a founder mutation; the remaining 3 patients were of unknown ethnic origin and were lost to follow-up. Screening of 758 European Roma controls for the R234C variant identified a carrier frequency of 3.5% among the Spanish Roma.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From SIB Swiss Institute of Bioinformatics, SCV000930062.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration 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-Strong : PP1 (segregation data) upgraded in strength to Strong (PMID:29950440).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV003786394.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 617681). This missense change has been observed in individuals with autosomal recessive centronuclear myopathy (PMID: 29950440). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs777176261, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the BIN1 protein (p.Arg234Cys).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024