Gene Validity Curation

CC2D1A - complex neurodevelopmental disorder

Gene: CC2D1A (HGNC:30237)
Classification - 01/08/2020
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: CC2D1A was reported in relation to autosomal recessive complex neurodevelopmental disorder in 2005 by Basel-Vanagaite (PMID: 16033914). At least 5 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and segregation data. Experimental data supporting this gene-disease relationship includes mouse models and expression studies. In summary, CC2D1A is definitively associated with autosomal recessive complex neurodevelopmental disorder. 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 6
10.5
10.5
McSherry M et al. 2018 Nov 30 (PMID:30500859); Reuter MS et al. 2017 Mar 1 (PMID:28097321); Manzini MC et al. 2014 Aug 7 (PMID:25066123); Basel-Vanagaite L et al. 2006 Mar (PMID:16033914);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
0
Loviglio MN et al. 2016 Nov 1 (PMID:27799067);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 4.61 2
Manzini MC et al. 2014 Aug 7 (PMID:25066123); Basel-Vanagaite L et al. 2006 Mar (PMID:16033914);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.61    
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) 11.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 0.5
Manzini MC et al. 2014 Aug 7 (PMID:25066123); Basel-Vanagaite L et al. 2006 Mar (PMID:16033914);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Manzini MC et al. 2014 Aug 7 (PMID:25066123); Oaks AW et al. 2017 Feb 1 (PMID:26826102);
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) 4.5

 


 

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 11.5 4.5 16 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
01/08/2020
EXPERT CURATION (DATE)
Definitive
01/08/2020
EVIDENCE SUMMARY
CC2D1A was reported in relation to autosomal recessive complex neurodevelopmental disorder in 2005 by Basel-Vanagaite (PMID: 16033914). At least 5 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and segregation data. Experimental data supporting this gene-disease relationship includes mouse models and expression studies. In summary, CC2D1A is definitively associated with autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.