Gene Validity Curation

HPD - tyrosinemia type III

Gene: HPD (HGNC:5147)
Classification - 06/29/2020
Disease: tyrosinemia type III (MONDO_0010162)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: HPD was first reported in relation to autosomal recessive Tyrosinemia Type 3 in 2000 (Rüetschi et al., 2000; PMID: 10942115). Tyrosinemia is primarily a biochemical phenotype with elevated tyrosine, 4-hydroxyphenylpyruvate, and its derivatives; it remains unclear if tyrosinemia type III is a predisposing factor that is strongly associated with cognitive delays, or if the association is purely on the basis of ascertainment bias. At least 7 unique variants (4 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 7 probands in 5 publications (PMIDs: 10942115, 11073718, 28649543, 23036342, 31901053). 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 metabolic 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, HPD is definitively associated with autosomal recessive Tyrosinemia Type 3. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (partial verses full loss of function), inheritance pattern (autosomal dominant verses recessive), and phenotypic variability (biochemical phenotype verses clinical manifestations). Therefore, we have split curations for the disease entities, Tyrosinemia type III and Hawkinsinuria.
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
4.5
5.35
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 4
0.85
Rüetschi U et al. 2000 Jun (PMID:10942115); Tomoeda K et al. 2000 Nov (PMID:11073718); Szymanska E et al. 2015 Dec (PMID:28649543); Tong F et al. 2019 Jun 25 (PMID:31901053);
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) 5.35
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
2
2
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
2
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) 6

 


 

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 5.35 6 11.35 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
05/29/2020
EXPERT CURATION (DATE)
Definitive
06/29/2020
EVIDENCE SUMMARY
HPD was first reported in relation to autosomal recessive Tyrosinemia Type 3 in 2000 (Rüetschi et al., 2000; PMID: 10942115). Tyrosinemia is primarily a biochemical phenotype with elevated tyrosine, 4-hydroxyphenylpyruvate, and its derivatives; it remains unclear if tyrosinemia type III is a predisposing factor that is strongly associated with cognitive delays, or if the association is purely on the basis of ascertainment bias. At least 7 unique variants (4 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 7 probands in 5 publications (PMIDs: 10942115, 11073718, 28649543, 23036342, 31901053). 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 metabolic 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, HPD is definitively associated with autosomal recessive Tyrosinemia Type 3. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (partial verses full loss of function), inheritance pattern (autosomal dominant verses recessive), and phenotypic variability (biochemical phenotype verses clinical manifestations). Therefore, we have split curations for the disease entities, Tyrosinemia type III and Hawkinsinuria.