Submission Details

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.

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].