Gene Validity Curation

BIN1 - myopathy, centronuclear, 2

Gene: BIN1 (HGNC:1052)
Classification - 06/26/2020
Disease: myopathy, centronuclear, 2 (MONDO_0009709)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Congenital Myopathies EP
Evidence Summary: Variants in the BIN1 gene have been reported in over twenty probands with autosomal recessive centronuclear myopathy in five different publications. Eight unique variants predicted to cause a loss of function of the protein have been reported, suggesting homozygous loss of function is the mechanism of disease. This gene-disease relationship is further supported by expression, protein-protein interaction, functional alteration, and animal model studies. In summary, ​BIN1​​ is definitively associated with ​autosomal recessive centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Five BIN1 variants described in two publications (PMID 25260562 and PMID 27854204) have been associated with autosomal dominant centronuclear myopathy, however the phenotype is more mild and onset occurs in adulthood. To date, the variants reported in association with autosomal dominant BIN1-associated centronuclear myopathy do not overlap with those observed in individuals with autosomal recessive BIN1-associated centronuclear myopathy and act through a distinct pathomechanism than recessive BIN1 variants. Given this information, the association between BIN1 and autosomal dominant centronuclear myopathy will be evaluated in a separate curation.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 3
5.5
12
Nicot AS et al. 2007 Sep (PMID:17676042); Böhm J et al. 2013 Jun (PMID:23754947); Böhm J et al. 2010 Dec 3 (PMID:21129173);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
6.5
Mejaddam AY et al. 2009 Dec (PMID:20476667); Claeys KG et al. 2010 Feb 9 (PMID:20142620); Nicot AS et al. 2007 Sep (PMID:17676042); Cabrera-Serrano M et al. 2018 July 24 (PMID:29950440);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.45 1
Cabrera-Serrano M et al. 2018 July 24 (PMID:29950440);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.45    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2 1 0.5
Kojima C et al. 2004 Nov 10 (PMID:15483625);
Expression 0.5 0 - 2 1 0.5
Butler MH et al. 1997 Jun 16 (PMID:9182667);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 7 4
Böhm J et al. 2013 Jun (PMID:23754947); Cowling BS et al. 2017 Dec 1 (PMID:29130937); Razzaq A et al. 2001 Nov 15 (PMID:11711432); Smith LL et al. 2014 Jul 1 (PMID:24549043);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
3.5
Razzaq A et al. 2001 Nov 15 (PMID:11711432); Smith LL et al. 2014 Jul 1 (PMID:24549043);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5 17 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
01/27/2020
EXPERT CURATION (DATE)
Definitive
06/26/2020
EVIDENCE SUMMARY
Variants in the BIN1 gene have been reported in over twenty probands with autosomal recessive centronuclear myopathy in five different publications. Eight unique variants predicted to cause a loss of function of the protein have been reported, suggesting homozygous loss of function is the mechanism of disease. This gene-disease relationship is further supported by expression, protein-protein interaction, functional alteration, and animal model studies. In summary, ​BIN1​​ is definitively associated with ​autosomal recessive centronuclear myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Five BIN1 variants described in two publications (PMID 25260562 and PMID 27854204) have been associated with autosomal dominant centronuclear myopathy, however the phenotype is more mild and onset occurs in adulthood. To date, the variants reported in association with autosomal dominant BIN1-associated centronuclear myopathy do not overlap with those observed in individuals with autosomal recessive BIN1-associated centronuclear myopathy and act through a distinct pathomechanism than recessive BIN1 variants. Given this information, the association between BIN1 and autosomal dominant centronuclear myopathy will be evaluated in a separate curation.