The relationship between PRODH2 and hydroxyprolinemia, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August 21st, 2019. Hydroxyprolinemia is a benign condition. Most individuals are identified by newborn screening because the mass spectra of hydroxyproline, isoleucine and leucine cannot be differentiated, resulting in false positive screening results for maple syrup urine disease in individuals with hydroxyprolinemia. PRODH2 encodes hydroxyproline dehydrogenase, which converts hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate. Biallelic variants in PRODH2 causing hydroxyprolinemia were first reported by Staufner et al in 2016 (PMID 27139199); this is currently the only available publication reporting variants in PRODH2 in individuals with hydroxyprolinemia. Data from 5 patients who are homozygous or compound heterozygous for PRODH2 variants were curated, including 7 unique variants (missense, nonsense, inframe deletion). Of note, an individual with a heterozygous missense variant in PRODH2 and a very mildly elevated hydroxyproline level was also reported. However, further studies are required to determine whether heterozygous variants in this gene are consistently associated with hydroxyprolinemia. An individual with hydroxyprolinemia and no identified PRODH2 variants was also reported, suggesting that other genes may also be involved. However, biochemical evidence is consistent with a defect in PRODH2. This gene-disease relationship is supported by the biochemical function of hydroxyproline dehydrogenase, which is consistent with the elevation of hydroxyproline observed in affected individuals (Carnie et al, 1982, PMID 7083820). In summary, there is limited 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. It was reevaluated on 10/14/2022 with one added article citing a knock out mouse model. As a result of this reevaluation, the classification remained Limited.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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