Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HPD : tyrosinemia type III

HGNC:5147 | MONDO_0010162
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 3
Rüetschi U et al. 2000 Jun (PMID:10942115); Heylen E et al. 2012 Nov (PMID:23036342);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Rüetschi U et al. 2000 Jun (PMID:10942115); Tomoeda K et al. 2000 Nov (PMID:11073718);
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) 5
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
Fellman JH et al. 1972 Sep 19 (PMID:4627454);
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 4
Endo F et al. 1995 Jan 1 (PMID:7774914);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
Kubo S et al. 1997 Jan 1 (PMID:8989996);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5



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 5 4.5 9.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
HPD was first reported in relation to autosomal recessive Tyrosinemia Type 3 in 2000 (Rüetschi et al., 2000; PMID: 10942115). At least 6 unique variants (3 missense, 2 nonsense, and 1 splicing) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 6 probands in 4 publications (PMIDs: 10942115, 11073718, 28649543, 23036342). Variants in this gene segregated with disease in 2 additional family members. Of note, this gene has been implicated in autosomal dominant Hawkinsinuria, in which the primary presentation is chronic acidosis and a single reported pathogenic mutation has been identified. This will be assessed separately. The gene disease relationship is supported by biochemical function, animal models, and rescue experiments. The biochemical function of HPD in tyrosine metabolism accounts for the typical high plasma tyrosine and high levels of 4-hydroxyphenylpyruvate and its derivatives in urine of Tyrosinemia Type 3 patients. A homozygous loss of function mouse exhibits similar biochemical phenotypes which can be rescued by adenoviral expression of human HPD. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.