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NM_139343.3(BIN1):c.461G>A (p.Arg154Gln) AND Myopathy, centronuclear, 2

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Jan 19, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000008798.13

Allele description [Variation Report for NM_139343.3(BIN1):c.461G>A (p.Arg154Gln)]

NM_139343.3(BIN1):c.461G>A (p.Arg154Gln)

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.461G>A (p.Arg154Gln)
HGVS:
  • NC_000002.12:g.127068982C>T
  • NG_012042.1:g.43307G>A
  • NM_001320632.2:c.461G>A
  • NM_001320633.2:c.461G>A
  • NM_001320634.1:c.389G>A
  • NM_001320640.2:c.461G>A
  • NM_001320641.2:c.461G>A
  • NM_001320642.1:c.380G>A
  • NM_004305.4:c.461G>A
  • NM_139343.3:c.461G>AMANE SELECT
  • NM_139344.3:c.461G>A
  • NM_139345.3:c.461G>A
  • NM_139346.3:c.461G>A
  • NM_139347.3:c.461G>A
  • NM_139348.3:c.461G>A
  • NM_139349.3:c.461G>A
  • NM_139350.3:c.461G>A
  • NM_139351.3:c.461G>A
  • NP_001307561.1:p.Arg154Gln
  • NP_001307562.1:p.Arg154Gln
  • NP_001307563.1:p.Arg130Gln
  • NP_001307569.1:p.Arg154Gln
  • NP_001307570.1:p.Arg154Gln
  • NP_001307571.1:p.Arg127Gln
  • NP_004296.1:p.Arg154Gln
  • NP_647593.1:p.Arg154Gln
  • NP_647594.1:p.Arg154Gln
  • NP_647595.1:p.Arg154Gln
  • NP_647596.1:p.Arg154Gln
  • NP_647597.1:p.Arg154Gln
  • NP_647598.1:p.Arg154Gln
  • NP_647599.1:p.Arg154Gln
  • NP_647600.1:p.Arg154Gln
  • NP_647601.1:p.Arg154Gln
  • LRG_873t1:c.461G>A
  • LRG_873:g.43307G>A
  • LRG_873p1:p.Arg154Gln
  • NC_000002.11:g.127826558C>T
  • NM_004305.3:c.461G>A
  • NM_139343.2:c.461G>A
Protein change:
R127Q; ARG154GLN
Links:
OMIM: 601248.0004; dbSNP: rs267606681
NCBI 1000 Genomes Browser:
rs267606681
Molecular consequence:
  • NM_001320632.2:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320633.2:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320634.1:c.389G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320640.2:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320641.2:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320642.1:c.380G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004305.4:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139343.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139344.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139345.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139346.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139347.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139348.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139349.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139350.3:c.461G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_139351.3:c.461G>A - 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
SCV000029008OMIM
no assertion criteria provided
Pathogenic
(Feb 9, 2010)
germlineliterature only

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

SCV000930065SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

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

PubMed (3)
[See all records that cite these PMIDs]

SCV001375361Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 19, 2024)
germlineclinical testing

PubMed (4)
[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

Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation.

Claeys KG, Maisonobe T, Böhm J, Laporte J, Hezode M, Romero NB, Brochier G, Bitoun M, Carlier RY, Stojkovic T.

Neurology. 2010 Feb 9;74(6):519-21. doi: 10.1212/WNL.0b013e3181cef7f9. No abstract available.

PubMed [citation]
PMID:
20142620
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000029008.2

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

Description

In a 21-year-old Moroccan man with autosomal recessive centronuclear myopathy (CNM2; 255200) beginning in childhood, Claeys et al. (2010) identified a homozygous 461G-A transition in exon 6 of the BIN1 gene, resulting in an arg154-to-gln (R154Q) substitution in a conserved residue in the BAR domain. The mutation was not present in 280 normal controls. The patient had diffuse muscle weakness and atrophy and mild mental retardation.

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

From SIB Swiss Institute of Bioinformatics, SCV000930065.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

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. PS3 : Well-established functional studies show a deleterious effect (PMID:24755653). 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.

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

From Invitae, SCV001375361.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 154 of the BIN1 protein (p.Arg154Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy (PMID: 20142620). ClinVar contains an entry for this variant (Variation ID: 8300). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BIN1 function (PMID: 24755653, 25262827). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Feb 20, 2024