Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FAH : tyrosinemia type I

HGNC:3579 | MONDO_0010161
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
Grompe M et al. 1993 (PMID:8318997); Rootwelt H et al. 1994 Oct (PMID:7942842); St-Louis M et al. 1994 Jan (PMID:8162054); Hahn SH et al. 1995 (PMID:7550234); Cao YY et al. 2012 Jun (PMID:22884142);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
Rootwelt H et al. 1994 Oct (PMID:7942842);
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
Kvittingen EA et al. 1981 Sep (PMID:7296877);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Tanguay RM et al. 1990 Aug (PMID:2378356);
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 3 4
Grompe M et al. 1993 Dec (PMID:8253378); Aponte JL et al. 2001 Jan 16 (PMID:11209059);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
Overturf K et al. 1997 Mar 20 (PMID:9095403); Yin H et al. 2016 Mar (PMID:26829318);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5 17 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
FAH was first reported in relation to autosomal recessive Tyrosinemia Type I in 1992 (Phaneuf et al. PMID: 1401056). At least 84 variants (including many missense, nonsense and splicing defects, as well as deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 16 probands in 5 publications (PMIDs: 22884142, 8318997, 7550234, 7942842, 8162054). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Summary of Experimental Evidence: 5 POINTS The gene-disease association is supported by the biochemical function of FAH, which catalyzes the cleavage of fumarylacetoacetate to fumarate and acetoacetate (PMID: 7296877); its absence results in the accumulation of fumarylacetoacetate and maleylacetoacetate, which are alkylating agents presumed responsible for the liver damage observed in Tyrosinemia Type I. Expression of FAH occurs primarily in the liver (and to a lesser degree kidneys and adrenals), which is the primary organ system affected by Tyrosinemia I, and is absent or reduced in acute and chronic patients respectively (PMID: 2378356). Mouse models have been generated both by targeted disruption of FAH and ENU-induced mutation (PMIDs: 8253378, 1129059). Both of these mouse models have been rescued by a variety of methods, including adenoviral vectors to introduce the human FAH gene and CRISPR to correct the mouse gene (PMIDs: 9095403, 26829318). In summary, FAH is definitively associated with autosomal recessive Tyrosinemia Type I. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.