Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PSAT1 : neurometabolic disorder due to serine deficiency

HGNC:19129 | 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 3
Hart CE et al. 2007 May (PMID:17436247); Glinton KE et al. 2018 Mar (PMID:29269105); 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 6
Brassier A et al. 2016 Jan (PMID:26610677); El-Hattab AW et al. 2016 May (PMID:26960553); Acuna-Hidalgo R et al. 2014 Sep 4 (PMID:25152457);
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) 7.75
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
Baek JY et al. 2003 Jul 1 (PMID:12633500);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Baek JY et al. 2003 Jul 1 (PMID:12633500);
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) 2



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 7.75 2 9.75 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
PSAT1 was first reported in relation to autosomal recessive neurometabolic disorder due to serine deficiency in 2007 (Hart CE, et al., PMID: 17436247; reported as phosphoserine aminotransferase deficiency). At least 7 unique variants (missense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 9 probands in 5 publications (PMIDs: 26610677, 26960553, 25152457, 17436247, 29269105). Variants in this gene segregated with disease in 1 additional family member. This gene-disease association is supported by the biochemical function of PSAT1 as a phosphoserine aminotransferase, its tissue enhanced expression in the brain, and a knockout mouse model. Of note, this gene has also been implicated in two neurometabolic disorders due to serine deficiency, phosphoserine aminotransferase 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 moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.