Gene Validity Curation

MCCC2 - 3-methylcrotonyl-CoA carboxylase deficiency

Gene: MCCC2 (HGNC:6937)
Classification - 10/25/2019
Disease: 3-methylcrotonyl-CoA carboxylase deficiency (MONDO_0018950)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: The relationship between MCCC2 and 3-methylcrotonyl-CoA carboxylase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of September, 2019. MCCC2 encodes the beta subunit of 3-methylcrotonyl-CoA carboxylase, which is involved in the catabolism of leucine. Deficiency of MCCC2 is associated with increased urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine, The clinical phenotype ranges from severe neurological abnormalities and death in infancy to asymptomatic. Variants in MCCC2 were first reported in humans with this deficiency in 2001 (Gallardo et al., PMID: 11170888; Baumgartner et al., PMID: 11181649). At least 113 unique variants (missense, nonsense, frameshift, splicing, deletion) have been identified in humans (Cozzolino et al., 2018; PMID 29767664). Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays, expression studies, and in vitro studies. In summary, MCCC2 is definitively associated with autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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 7
14
12
Uematsu M et al. 2007 Oct 30 (PMID:17968484); Fonseca H et al. 2016 Dec 15 (PMID:27601257); Grünert SC et al. 2012 May 29 (PMID:22642865); Gallardo ME et al. 2001 Feb (PMID:11170888);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
0.5
Grünert SC et al. 2012 May 29 (PMID:22642865);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
0.5
1
Baumgartner MR et al. 2001 Feb (PMID:11181649);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Gallardo ME et al. 2001 Feb (PMID:11170888);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Gallardo ME et al. 2001 Feb (PMID:11170888);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2

 


 

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 2 14 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
09/18/2019
EXPERT CURATION (DATE)
Definitive
10/25/2019
EVIDENCE SUMMARY
The relationship between MCCC2 and 3-methylcrotonyl-CoA carboxylase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of September, 2019. MCCC2 encodes the beta subunit of 3-methylcrotonyl-CoA carboxylase, which is involved in the catabolism of leucine. Deficiency of MCCC2 is associated with increased urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine, The clinical phenotype ranges from severe neurological abnormalities and death in infancy to asymptomatic. Variants in MCCC2 were first reported in humans with this deficiency in 2001 (Gallardo et al., PMID: 11170888; Baumgartner et al., PMID: 11181649). At least 113 unique variants (missense, nonsense, frameshift, splicing, deletion) have been identified in humans (Cozzolino et al., 2018; PMID 29767664). Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays, expression studies, and in vitro studies. In summary, MCCC2 is definitively associated with autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.