rs2904551
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PS1_ModeratePP5BP4BS2
The NM_016335.6(PRODH):āc.1322T>Cā(p.Leu441Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L441Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_016335.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRODH | NM_016335.6 | c.1322T>C | p.Leu441Pro | missense_variant | 11/14 | ENST00000357068.11 | |
PRODH | NM_001195226.2 | c.998T>C | p.Leu333Pro | missense_variant | 11/14 | ||
PRODH | NM_001368250.2 | c.998T>C | p.Leu333Pro | missense_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRODH | ENST00000357068.11 | c.1322T>C | p.Leu441Pro | missense_variant | 11/14 | 1 | NM_016335.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00253 AC: 29AN: 11466Hom.: 0 Cov.: 3
GnomAD3 exomes AF: 0.00521 AC: 1303AN: 249888Hom.: 12 AF XY: 0.00507 AC XY: 686AN XY: 135246
GnomAD4 exome AF: 0.00392 AC: 748AN: 190684Hom.: 50 Cov.: 0 AF XY: 0.00387 AC XY: 388AN XY: 100218
GnomAD4 genome ? AF: 0.00253 AC: 29AN: 11484Hom.: 0 Cov.: 3 AF XY: 0.00197 AC XY: 10AN XY: 5078
ClinVar
Submissions by phenotype
Proline dehydrogenase deficiency Pathogenic:2Uncertain:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2005 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.732>=0.6, 3CNET: 0.975>=0.75). A missense variant is a common mechanism associated with Hyperprolinemia, type I. Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000004008, PMID:12217952). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 29, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 441 of the PRODH protein (p.Leu441Pro). This variant is present in population databases (rs2904551, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PRODH protein function. Experimental studies have shown that this missense change affects PRODH function (PMID: 15662599). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 29, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
not provided Pathogenic:2Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 19, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PRODH p.Leu441Pro variant was identified in 4 of 934 proband chromosomes (frequency: 0.0043) from individuals or families with schizophrenia (Jacquet_2002_PMID:12217952; Jacquet_2005_PMID:1549470). This variant was also identified as a homozygous variant in two unrelated children with severe type I hyperprolinemia with neurological manifestations (Jacquet_2002_PMID:12217952). In transient transfection assays, this variant was found to severely (>70%) reduce POX activity (Bender_2005_PMID:15662599). The variant was identified in dbSNP (ID: rs2904551), LOVD 3.0 (classified as a VUS and pathogenic) and ClinVar (classified as likely pathogenic by GeneDx, Center for Pediatric Genomic Medicine Children's Mercy Hospital and Clinics and CeGaT Praxis fuer Humangenetik Tuebingen, and as uncertain significance by Invitae for Proline dehydrogenase deficiency). The variant was identified in control databases in 1454 of 281208 chromosomes (13 homozygous) at a frequency of 0.005171 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 231 of 35338 chromosomes (freq: 0.006537), Other in 46 of 7194 chromosomes (freq: 0.006394), East Asian in 117 of 19810 chromosomes (freq: 0.005906), Ashkenazi Jewish in 57 of 10298 chromosomes (freq: 0.005535), European (non-Finnish) in 639 of 128296 chromosomes (freq: 0.004981), African in 118 of 24764 chromosomes (freq: 0.004765), South Asian in 136 of 30462 chromosomes (freq: 0.004465), and European (Finnish) in 110 of 25046 chromosomes (freq: 0.004392). The p.Leu441 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2016 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | PRODH: PP3, PS3:Supporting, PS4:Supporting - |
Schizophrenia 4 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 27, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP4. This variant was detected in homozygous state. - |
risk factor, no assertion criteria provided | literature only | OMIM | Mar 01, 2005 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2020 | The c.1322T>C (p.L441P) alteration is located in exon 12 (coding exon 11) of the PRODH gene. This alteration results from a T to C substitution at nucleotide position 1322, causing the leucine (L) at amino acid position 441 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the PRODH c.1322T>C alteration was observed in 0.52% (1454/281208) of total alleles studied, with a frequency of 0.65% (231/35338) in the Latino subpopulation. This alteration has been reported in the homozygous state as well as in trans with other alterations in patients with hyperprolinemia who also had neurological symptoms (Jacquet, 2002; Afenjar, 2007; Guilmatre, 2010). This alteration was significantly associated with hyperprolinemia in a case-control study (Jacquet, 2005). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration results in a severe reduction of proline oxidase (POX) activity and reduced stability (Zhang, 2004; Bender, 2005). The in silico prediction for the p.L441P alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 17, 2024 | Variant summary: PRODH c.1322T>C (p.Leu441Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 249888 control chromosomes in the gnomAD database, including 12 homozygotes. c.1322T>C has been reported in the literature in individuals affected with Proline Dehydrogenase Deficiency, hyperprolinemia and autistic feature (example, Jacquet_2002, Minardi_2020, Raux_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Proline Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in less than 10% of enzymatic activity WT in vitro and inability to increase intracellular ROS levels (Nagano_2017). The following publications have been ascertained in the context of this evaluation (PMID: 12217952, 32725632, 28264926, 17135275). ClinVar contains an entry for this variant (Variation ID: 4008). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at