Gene Validity Curation

HIBCH - neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency

Gene: HIBCH (HGNC:4908)
Classification - 11/07/2019
Disease: neurodegeneration due to 3-hydroxyisobutyryl-CoA hydrolase deficiency (MONDO_0009603)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: The relationship between HIBCH and 3-hydroxyisobutyryl-CoA hydrolase deficiency (Autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of 09/12/19. Variants in HIBCH were first reported in humans with this disease as early as 2007 (Loupatty et al., PMID: 17160907). At least 12 variants (e.g. missense, frameshift, and splice-site) have been reported in humans. Evidence supporting this gene-disease relationship includes predominantly case-level data with some experimental data. Variants in this gene have been reported in at least 8 probands in 7 publications (24299452, 30847210, 17160907, 26163321, 26026795, 29703962, 27896122). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function, with the loss of HIBCH causing Methacrylyl-CoA and its conjugates to build up in the brain and other tissues and disrupt mitochondrial function. This gene-disease association is also supported by two pieces of biochemical function evidence, but with no models or functional evidence being available. In summary, HIBCH is definitively associated with autosomal recessive 3-hydroxyisobutyryl-CoA hydrolase deficiency. Although there is the maximum amount of genetic evidence, further experimental evidence would be valuable to better understand this gene-disease relationship.
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 4
10
12
Loupatty FJ et al. 2007 Jan (PMID:17160907); Tan H et al. 2018 Jul (PMID:29703962); Peters H et al. 2015 Aug (PMID:26163321);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
4
Ferdinandusse S et al. 2013 Dec 4 (PMID:24299452); Yamada K et al. 2014 Oct 16 (PMID:27896122); Stiles AR et al. 2015 Aug (PMID:26026795); Karimzadeh P et al. 2019 Feb (PMID:30847210);
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 2
1
1
Loupatty FJ et al. 2007 Jan (PMID:17160907); Peters H et al. 2015 Aug (PMID:26163321);
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
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) 1

 


 

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 1 13 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
11/07/2019
EXPERT CURATION (DATE)
Definitive
11/07/2019
EVIDENCE SUMMARY
The relationship between HIBCH and 3-hydroxyisobutyryl-CoA hydrolase deficiency (Autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of 09/12/19. Variants in HIBCH were first reported in humans with this disease as early as 2007 (Loupatty et al., PMID: 17160907). At least 12 variants (e.g. missense, frameshift, and splice-site) have been reported in humans. Evidence supporting this gene-disease relationship includes predominantly case-level data with some experimental data. Variants in this gene have been reported in at least 8 probands in 7 publications (24299452, 30847210, 17160907, 26163321, 26026795, 29703962, 27896122). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function, with the loss of HIBCH causing Methacrylyl-CoA and its conjugates to build up in the brain and other tissues and disrupt mitochondrial function. This gene-disease association is also supported by two pieces of biochemical function evidence, but with no models or functional evidence being available. In summary, HIBCH is definitively associated with autosomal recessive 3-hydroxyisobutyryl-CoA hydrolase deficiency. Although there is the maximum amount of genetic evidence, further experimental evidence would be valuable to better understand this gene-disease relationship.