Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PHGDH : neurometabolic disorder due to serine deficiency

HGNC:8923 | 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 2
Poli A et al. 2017 Jul (PMID:28440900); Mattos EP et al. 2015 Jun (PMID:25913727);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 11
Klomp LW et al. 2000 Dec (PMID:11055895); Tabatabaie L et al. 2009 May (PMID:19235232); Méneret A et al. 2012 Jul (PMID:22393170); Benke PJ et al. 2017 May (PMID:28135894); Acuna-Hidalgo R et al. 2014 Sep 4 (PMID:25152457); Shaheen R et al. 2014 Jun 5 (PMID:24836451);
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 1
Achouri Y et al. 1997 Apr 15 (PMID:9163325);
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 2
Yoshida K et al. 2004 Jan 30 (PMID:14645240);
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) 2.5



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 2.5 14.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
PHGHD was first reported in relation to autosomal recessive neurometabolic disorder due to serine deficiency in 2000 (Klomp LW, et al., PMID: 11055895; reported 3-phosphoglycerate dehydrogenase deficiency). At least 20 unique variants (missense and small indels) 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 13 probands in 8 publications (PMIDs: 19235232, 24836451, 28440900, 22393170, 25913727, 11055895, 28135894, 25152457). Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the biochemical function of PHGDH as the 3-phosphoglycerate dehydrogenase and a knockout mouse model. Of note, this gene has also been implicated in two neurometabolic disorders due to serine deficiency, 3-phosphoglycerate dehydrogenase 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, PHGDH is definitively associated with autosomal recessive neurometabolic disorder due to serine deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.