PHGDH
protein-codingphosphoglycerate dehydrogenase
Gene summary
This gene encodes the enzyme which is involved in the early steps of L-serine synthesis in animal cells. L-serine is required for D-serine and other amino acid synthesis. The enzyme requires NAD/NADH as a cofactor and forms homotetramers for activity. Mutations in this gene have been found in a family with congenital microcephaly, psychomotor retardation and other symptoms. Multiple alternatively spliced transcript variants have been found, however the full-length nature of most are not known. [provided by RefSeq, Aug 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~95.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011152
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011152
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011152
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009736
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011152
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018162
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0018162
Submitter: ClinGen
*PHGDH* was first reported in relation to an 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 and included in this curation. 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). 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. This classification was approved by the ClinGen Aminoacidopathy GCEP on June 29, 2020 (SOP Version 7). Supplementary remarks provided by the Prenatal GCEP: Biallelic variants in PHGDH lead to a disorder with phenotypic variability. The severe presentation, classically defined as Neu-Laxova syndrome is characterized prenatally by severe fetal growth restriction, skeletal anomalies including contractures with or without pterygia, cataracts, dysmorphic features, collodion-like ichthyosis, variable MRI findings including lissencephaly, hydrocephalus, and cerebellar hypoplasia, microcephaly, and in severe cases, pre- or perinatal lethality. Individuals with biallelic pathogenic variants in *PHGDH* and relevant prenatal phenotypes have been described in multiple publications with missense, nonsense, frameshift, and canonical splice variants described [PMID:24836451, 25913727, 26610677, 30838783, 31903955, 32579715]. Infantile onset *PHGDH* deficiency is characterized by neurodevelopmental delay, intellectual disability, spastic tetraparesis, microcephaly, variable MRI findings, epilepsy, and may also be associated with intrauterine growth restriction and congenital microcephaly [PMID:28440900].
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Dermatologic; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Pulmonary
Intervention: Biochemical
Rationale: Amino acid therapy (eg, with L-serine, glycine) has been reported as beneficial for at least some clinical parameters, especially if early treatment is inititiated (reports include benefits to prenatal treatment)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PHGDH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006623.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 9 | 274 | 1 | 284 | ||
| missense | 4 | 14 | 279 | 11 | 308 | |
| nonsense | 13 | 20 | 33 | |||
| start loss | 3 | 3 | ||||
| frameshift | 61 | 15 | 2 | 78 | ||
| splice donor/acceptor (+/-2bp) | 1 | 18 | 2 | 21 | ||
| Total | 79 | 70 | 292 | 285 | 1 | 727 |
Highest pathogenic variant AF is 0.00006382878
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006614.2 | 12 | MANE Select | |
| Ensembl | ENSP00000493175.1 | 12 | MANE Select | |
| Ensembl | ENSP00000358417.5 | 12 | Standard | |
| Ensembl | ENSP00000358417.5 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycine, serine and threonine metabolism - Homo sapiens (human)
- 3-Phosphoglycerate dehydrogenase deficiency
- Non Ketotic Hyperglycinemia
- Glycine and Serine Metabolism
- Dimethylglycine Dehydrogenase Deficiency
Biological Process
- cellular amino acid metabolic process
- glutamine metabolic process
- glycine metabolic process
- L-serine biosynthetic process
- threonine metabolic process
Molecular Function
- phosphoglycerate dehydrogenase activity
- electron transfer activity
- L-malate dehydrogenase activity
- NAD binding
Cellular Component
- cytosol
- myelin sheath
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000369409
- Coding exons
- 12
- Length
- 84418
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 26
- Defined
- 125748
- p
- 0.000103
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.207 | 295 | 305 | 0.967 | 0.0000185 | 3421 |
| Missense (PolyPhen) | 98 | 105.97 | 0.92477 | 1184 | ||
| Synonymous | -0.572 | 139 | 131 | 1.06 | 0.00000828 | 1151 |
| Loss of Function | 2.34 | 10 | 21.8 | 0.459 | 0.00000104 | 260 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the reversible oxidation of 3-phospho-D- glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate. {ECO:0000269|PubMed:11751922, ECO:0000269|PubMed:25406093}.;
- Disease
- DISEASE: Phosphoglycerate dehydrogenase deficiency (PHGDHD) [MIM:601815]: An autosomal recessive inborn error of L-serine biosynthesis, clinically characterized by congenital microcephaly, psychomotor retardation, and seizures. {ECO:0000269|PubMed:11055895, ECO:0000269|PubMed:19235232}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neu-Laxova syndrome 1 (NLS1) [MIM:256520]: A lethal, autosomal recessive multiple malformation syndrome characterized by ichthyosis, marked intrauterine growth restriction, microcephaly, short neck, limb deformities, hypoplastic lungs, edema, and central nervous system anomalies including lissencephaly, cerebellar hypoplasia and/or abnormal/agenesis of the corpus callosum. Abnormal facial features include severe proptosis with ectropion, hypertelorism, micrognathia, flattened nose, and malformed ears. {ECO:0000269|PubMed:24836451}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.562
Intolerance Scores
- LoFtool
- 0.151
- RVIS EVS
- -0.62
- RVIS percentile EVS
- 17.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.958
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |