Submission Details

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 4 probands in 4 publications (PMIDs: 26589312, 25080166, 14673469, 38816452). Variants in this gene segregated with disease in 5 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 moderate 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.

This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 09/29/2020. It was reevaluated on 10/14/2022 and again on 12/10/2024 when one new case was identified (PMID: 38816452). As a result of this reevaluation, the classification remained Moderate.