Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CA5A : hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

HGNC:1377 | MONDO_0014332
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

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 9
10.5
12
van Karnebeek CD et al. 2014 Mar 6 (PMID:24530203); Diez-Fernandez C et al. 2016 Oct (PMID:26913920);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
2.5
van Karnebeek CD et al. 2014 Mar 6 (PMID:24530203); Diez-Fernandez C et al. 2016 Oct (PMID:26913920);
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
1
1
Sly WS et al. 1995 (PMID:7574487);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Shah GN et al. 2013 Apr 30 (PMID:23589845);
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) 3

 


 

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 3 15 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
02/07/2019
EXPERT CURATION (DATE)
Definitive
09/10/2018
EVIDENCE SUMMARY
The CA5A gene has been associated with autosomal recessive hyperammonemia due to carbonic anhydrase VA deficiency using the ClinGen Clinical Validity Framework. CA5A was first associated with this disease in humans in 2014 (Karnebeek et al, PMID 24530203), and the association has been reported in 13 probands in 2 publications (Karnebeek et al, 2014, PMID 24530203; Diez-Fernandez et al, 2016, PMID 26913920). Six variants (including two missense, one nonsense, one splice site, one intronic deletion, and a single exon deletion) have been described in humans. Of note, deletion of exon 6 has been reported in six probands, all of whom are from the Indian subcontinent. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the biochemical function of the gene product (carbonic anhydrase VA), and a mouse model (Shah et al, 2013, PMID 23589845). In summary, CA5A is definitively associated with autosomal recessive hyperammonemia due to carbonic anhydrase VA deficiency. This classification was approved by the ClinGen Aminoacidopathies Expert Panel of the Inborn Errors of Metabolic Working Group on September 10th, 2018.