Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PSPH : neurometabolic disorder due to serine deficiency

HGNC:9577 | MONDO_0018162
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 1
Acuna-Hidalgo R et al. 2014 Sep 4 (PMID:25152457);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
Byers HM et al. 2015 Nov 21 (PMID:26589312); Veiga-da-Cunha M et al. 2004 Feb (PMID:14673469); Vincent JB et al. 2015 Mar (PMID:25080166);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 2.78 1
Vincent JB et al. 2015 Mar (PMID:25080166);
Total Summed LOD Score 2.78    
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) 3.25
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
Collet JF et al. 1997 May 26 (PMID:9188776);
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 1 1
Dickinson ME et al. 2016 Sep 22 (PMID:27626380);
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) 1.5



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 3.25 1.5 4.75 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
PSPH was first reported in relation to autosomal recessive neurometabolic disorder due to serine deficiency in 2004 (Veiga-da-Cunha M, et al., PMID: 14673469; reported as phosphoserine phosphatase deficiency). At least 5 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 3 probands in 3 publications (PMIDs: 26589312, 25080166, 14673469). Variants in this gene segregated with disease in 4 additional family members. This gene-disease association is supported by the biochemical function of PSPH as a phosphoserine phosphatase and a knockout mouse model with prenatal lethality. Of note, this gene has been implicated in two neurometabolic disorders due to serine deficiency, phosphoserine phosphatase deficiency and Neu-Laxova syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no reported difference in molecular mechanisms or inheritance pattern and current assertions in the field suggest one broad phenotypic spectrum associated with serine biosynthesis defects encompassing both disorders (PMIDs: 28653176, 27161889, 26960553, 25152457). Therefore, all of the disease entities have been lumped into one disease entity, neurometabolic disorder due to serine deficiency. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.