Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

IVD : isovaleric acidemia

HGNC:6186 | MONDO_0009475
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 6
12
12
Couce ML et al. 2017 Mar (PMID:27904153); Vockley J et al. 1991 Jul (PMID:2063866); Cho JM et al. 2013 Aug (PMID:24019846);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 11
6
Couce ML et al. 2017 Mar (PMID:27904153); Vockley J et al. 1991 Jul (PMID:2063866);
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
0.5
Vockley J et al. 2006 May 15 (PMID:16602101);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Dubiel B et al. 1983 Nov (PMID:6630517);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Leandro J et al. 2019 Jan 24. (PMID:30709776);
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) 2.5

 


 

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 2.5 14.5 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
06/05/2019
EXPERT CURATION (DATE)
Definitive
05/10/2019
EVIDENCE SUMMARY
The relationship between IVD and isovaleric acidemia (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of April, 2019. Isovaleric acidemia (IVA) is an inborn error of leucine metabolism characterized by an accumulation of isovaleryl-CoA derivatives in cells, blood and urine. Clinical presentation varies widely from acute neonatal to chronic intermittent and can be detected by newborn screening. Variation in IBD were first identified in humans with the disease as early as 1985 (Ikeda et al., PMID 3863140). To date, over 50 unique variants (missense, nonsense, frameshift, splicing) have been reported (Sakamoto et al., 2015; PMID 26018748). This gene-disease relationship is supported by biochemical assays, in vitro assays, and a mouse model. In summary, IVD is definitively associated with autosomal recessive isovaleric acedmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.