Submission Details

The relationship between PRODH and hyperprolinemia type 1 (HP 1), an autosomal recessive disorder of proline metabolism, was evaluated using the ClinGen Clinical Validity Framework as of March 12, 2021. PRODH encodes proline oxidase/dehydrogenase a mitochondrial, inner membrane protein that catalyzes the first step in proline metabolism, converting proline to pyrroline-5-carboxylate (P5C). In the next step of the pathway, P5C dehydrogenase converts P5C to glutamate. Deficiency of proline oxidase is associated with HP1, which is characterized by 2-10 times the normal level of plasma proline and normal urinary P5C (Mitsubuchi et al, 2014, PMID: 24931297). Hyperprolinemia type II, caused by deficiency of P5C dehydrogenase, is characterized by 10-15 times the normal level of plasma proline and elevated P5C in urine. The clinical symptoms associated with HP1 are unclear; some individuals have no symptoms while others present with severe neurological features or nephropathy (Mitsubuchi et al, 2014, PMID: 24931297). PRODH is located on chromosome 22q11 in the region typically deleted in 22q11 deletion syndrome (DiGeorge syndrome, velocardiofacial syndrome). About 50% of patients with 22q11 deletion syndrome have elevated plasma proline, with levels 278-849 mmol/L (normal <270) (Goodman et al, 2000, PMID: 11196113; Jacquet et al, 2002, PMID: 12217952). Most of these individuals do not have an identifiable PRODH variant on the second allele, suggesting that haploinsufficiency of PRODH may be a factor in elevated proline levels. Of note, individuals with 22q11 deletion syndrome have an increased risk to develop schizophrenia. Some studies have suggested a link between PRODH, hyperprolinemia and schizophrenia (Willis et al, 2008, PMID: 18528746). A PRODH pseudogene with >95% sequence identity to PRODH exists and has accumulated several missense variants that have been transferred to PRODH, presumably by gene conversion (Liu et al, 2002, PMID: 11891283). Biallelic variants causing loss of function of PRODH were first reported in patients with hyperprolinemia type 1 in 2002 (Jacquet et al, PMID: 12217952). Six unique variants, predicted to impact the activity of proline oxidase, from 12 probands from seven publications were curated (Jacquet et al, 2002, PMID: 12217952; Jacquet et al, 2003, PMID: 12525555; Afenjar et al, 2007, PMID: 17412540; Di Rosa et al, 2008, PMID: 18197084; Jang et al, 2013, PMID: 23462603; Richard et al, 2016, PMID: 26978485; Duarte et al, 2017, PMID: 28202261). These variants included multigenic 22q11 deletions (causing 22q11 deletion syndrome – note that no other genes within this region are expected to affect proline levels), a 350 kb deletion that includes the entire PRODH gene, a nonsense variant, and various missense variants (p.Leu441Pro, p.Arg453Cys, p.Thr466Met) that recurred among patients. Patients with biallelic deletion of the entire PRODH gene had higher proline levels than those with biallelic missense variants, suggesting that the missense changes retain some level of residual enzyme activity in vivo, as evidenced by functional studies (Bender et al, 2005, PMID: 15662599). Of note, there are multiple homozygotes for all of these missense changes in gnomAD, which is consistent with hyperprolinemia being benign. In addition, many of these changes occur in cis with other missense changes and the true frequency of the haplotype, its impact on PRODH function as well as the frequency of hyperprolinemia in the population is unknown. In this curation, patients with more common missense changes were not scored due to the higher likelihood that they are benign. Of note, some individuals with heterozygous variants in PRODH may have mild-moderately elevated proline levels, suggesting that the causes of elevated proline may be complex (Jacquet et al, 2002; PMID: 12217952 The relationship between PRODH and hyperprolinemia type 1 is also supported by the biochemical function of proline oxidase in catalyzing the first step of proline metabolism which is, therefore, consistent with the finding of hyperprolinemia in patients with variants in PRODH (Tallarita et al, 2012, PMID: 22333530; Tanner et al, 2019, PMID: 28990412). In addition, a null mouse model has been made in which homozygotes have markedly elevated proline levels (Gogos et al, 1999, PMID: 10192398). In summary, PRODH is definitively associated with hyperprolinemia type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 27, 2021.