Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

AUH : 3-methylglutaconic aciduria type 1

HGNC:890 | MONDO_0009610
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
16
12
IJlst L et al. 2002 Dec (PMID:12434311); Ly TB et al. 2003 Apr (PMID:12655555); Illsinger S et al. 2004 Mar (PMID:15033206); Matsumori M et al. 2005 Dec (PMID:16354225); Eriguchi M et al. 2006 Nov 28 (PMID:17130438); Wortmann SB et al. 2010 Sep 21 (PMID:20855850); Tavasoli AR et al. 2017 Sep (PMID:28438368); Mercimek-Mahmutoglu S et al. 2011 Nov (PMID:21840233);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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
Mack M et al. 2006 May (PMID:16640564);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Mack M et al. 2006 May (PMID:16640564);
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
03/17/2019
EXPERT CURATION (DATE)
Definitive
03/08/2019
EVIDENCE SUMMARY
AUH was first reported in relation to autosomal recessive 3-methylglutaconic aciduria type 1 in 2002 (IJlst et al., PMID: 12434311). At least 11 unique variants (splicing errors, nonsense, frameshift, and missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 9 probands in 8 publications (PMIDs: 21840233, 28438368, 20855850, 17130438, 16354225, 15033206, 12655555, 12434311). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by the biochemical function of AUH as a 3-methylglutaconyl-CoA hydratase and its altered function in non-patient cells (PMID: 16640564). In summary, AUH is definitively associated with autosomal recessive 3-methylglutaconic aciduria type 1.