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.
ClinVar Genomic variation as it relates to human health
NM_139343.3(BIN1):c.461G>A (p.Arg154Gln)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(3)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)
Likely pathogenic(1); Uncertain significance(1)
3
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_139343.3(BIN1):c.461G>A (p.Arg154Gln)
Variation ID: 8300 Accession: VCV000008300.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q14.3 2: 127068982 (GRCh38) [ NCBI UCSC ] 2: 127826558 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 11, 2019 Feb 14, 2024 Jan 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_139343.3:c.461G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_647593.1:p.Arg154Gln missense NM_001320632.2:c.461G>A NP_001307561.1:p.Arg154Gln missense NM_001320633.2:c.461G>A NP_001307562.1:p.Arg154Gln missense NM_001320634.1:c.389G>A NP_001307563.1:p.Arg130Gln missense NM_001320640.2:c.461G>A NP_001307569.1:p.Arg154Gln missense NM_001320641.2:c.461G>A NP_001307570.1:p.Arg154Gln missense NM_001320642.1:c.380G>A NP_001307571.1:p.Arg127Gln missense NM_004305.4:c.461G>A NP_004296.1:p.Arg154Gln missense NM_139344.3:c.461G>A NP_647594.1:p.Arg154Gln missense NM_139345.3:c.461G>A NP_647595.1:p.Arg154Gln missense NM_139346.3:c.461G>A NP_647596.1:p.Arg154Gln missense NM_139347.3:c.461G>A NP_647597.1:p.Arg154Gln missense NM_139348.3:c.461G>A NP_647598.1:p.Arg154Gln missense NM_139349.3:c.461G>A NP_647599.1:p.Arg154Gln missense NM_139350.3:c.461G>A NP_647600.1:p.Arg154Gln missense NM_139351.3:c.461G>A NP_647601.1:p.Arg154Gln missense NC_000002.12:g.127068982C>T NC_000002.11:g.127826558C>T NG_012042.1:g.43307G>A LRG_873:g.43307G>A LRG_873t1:c.461G>A LRG_873p1:p.Arg154Gln - Protein change
- R154Q, R127Q, R130Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:127068981:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BIN1 | - | - |
GRCh38 GRCh37 |
704 | 754 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 19, 2024 | RCV000008798.14 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 08, 2019)
|
criteria provided, single submitter
Method: curation
|
Myopathy, centronuclear, 2
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000930065.1
First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019 |
Comment:
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 … (more)
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. (less)
|
|
|
Uncertain significance
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Myopathy, centronuclear, 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001375361.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
|
|
|
Pathogenic
(Feb 09, 2010)
|
no assertion criteria provided
Method: literature only
|
MYOPATHY, CENTRONUCLEAR, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029008.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 11, 2019 |
Comment on evidence:
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 … (more)
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. (less)
|
Comment:
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| N-WASP is required for Amphiphysin-2/BIN1-dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy. | Falcone S | EMBO molecular medicine | 2014 | PMID: 25262827 |
| Mutations in BIN1 associated with centronuclear myopathy disrupt membrane remodeling by affecting protein density and oligomerization. | Wu T | PloS one | 2014 | PMID: 24755653 |
| Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. | Claeys KG | Neurology | 2010 | PMID: 20142620 |
Text-mined citations for rs267606681 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.