ClinVar Miner

Submissions for variant NM_016335.5(PRODH):c.1322T>C (p.Leu441Pro) (rs2904551)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412946 SCV000490742 likely pathogenic not provided 2016-03-15 criteria provided, single submitter clinical testing The L441P variant in the PRODH gene has been reported previously in association with hyperprolinemia type I (Jacquet et al., 2002). The NHLBI ESP Exome Sequencing Project reports L441P was observed in 58/8600 alleles from individuals of European-American background, with no homozygous individuals reported. The L441P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show that the L441P variant leads to reduced stability of proline oxidase and significant reduction in its activity (Bender et al., 2005). The L441P variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000412946 SCV000493699 likely pathogenic not provided 2016-07-31 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000412946 SCV000609760 likely pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing
Invitae RCV000004218 SCV000631841 uncertain significance Proline dehydrogenase deficiency 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 441 of the PRODH protein (p.Leu441Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases where 5 homozygous individuals are also reported (rs2904551, ExAC 0.8%). This variant has been reported in individuals affected with type I hyperprolinemia and has been reported to be associated with neurological manifestations when present in the homozygous state. It is also reported to present at a higher frequency in affected individuals than unaffected controls in a small cohort from the French population (PMID: 12217952, 20524212). ClinVar contains an entry for this variant (Variation ID: 4008). Experimental studies have shown that this missense abrogates the PRODH enzymatic activity in vitro (PMID: 15662599). In summary, this variant is a rare missense change that has been found in affected individuals and has been shown to affect protein function. However, it is also found in the population at a high frequency. For these reasons, it has been classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196915 SCV001367549 pathogenic Seizures; Generalized seizures 2020-01-27 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. This variant was detected in homozygous state.
OMIM RCV000004218 SCV000024384 pathogenic Proline dehydrogenase deficiency 2005-03-01 no assertion criteria provided literature only
OMIM RCV000004219 SCV000024385 risk factor Schizophrenia 4 2005-03-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.