Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PTS : BH4-deficient hyperphenylalaninemia A

HGNC:9689 | MONDO_0009863
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
Thöny B et al. 1994 May (PMID:8178819); Oppliger T et al. 1997 (PMID:9222757); Meili D et al. 2009 May (PMID:19280650); Brasil S et al. 2011 Sep (PMID:21542064); Leuzzi V et al. 2010 Mar (PMID:20059486);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
Thöny B et al. 1994 May (PMID:8178819); Oppliger T et al. 1997 (PMID:9222757); Meili D et al. 2009 May (PMID:19280650);
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
Longo N et al. 2009 Jun (PMID:19234759);
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 3
Sumi-Ichinose C et al. 2001 Nov 2 (PMID:11517215);
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 1 1
Brasil S et al. 2011 Sep (PMID:21542064);
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 12 4.5 16.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between PTS and Biopterin-deficient hyperphenylalaninemia a, an autosomal recessive disorder of biopterin synthesis, was evaluated using the ClinGen Clinical Validity Framework as of December 22nd, 2017. PTS encodes 6-pyruvoyl-tetrahydropterin synthase (PTPS), which catalyzes the second step of biopterin synthesis. Hundreds of patients with deficiency of PTPS activity have been reported (Opladen et al, 2012, PMID 22729819). Variants in PTS were first reported in humans with this disease as early as 1994 (Thöny et al, PMID 8178819). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen unique variants (missense, frameshift, splice site, inframe deletion, and intronic variants resulting in pseudoexon inclusion) have been reported in humans. Variants in this gene were curated in 9 probands in 5 publications (Thöny et al, 1994; PMID 8178819; Oppliger et al, 1997, PMID 9222757; Meili et al, 2007, PMID 19280650; Leuzzi et al, 2010, PMID 20059486; Brasil et al, 2011, PMID 21542064). More evidence is available in the literature but the maximum score for genetic evidence (12 points ) has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the function of PTPS, which is consistent with the disease process, as well as the biochemical features of a null mouse model (Sumi-Ichinose et al, 2001, PMID 11517215). In summary, PTPS is definitively associated with Biopterin-deficient hyperphenylalaninemia a. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on December 22nd, 2017.