ClinVar Miner

Submissions for variant NM_016335.6(PRODH):c.930-1G>C

gnomAD frequency: 0.00017  dbSNP: rs751149776
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001959616 SCV002256406 likely pathogenic Proline dehydrogenase deficiency 2024-10-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the PRODH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PRODH are known to be pathogenic (PMID: 12525555, 15662599, 19736351). This variant is present in population databases (rs751149776, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PRODH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1466893). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV002307820 SCV002601368 uncertain significance not provided 2022-05-11 criteria provided, single submitter clinical testing Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002484841 SCV002783961 likely pathogenic Proline dehydrogenase deficiency; Schizophrenia 4 2024-04-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001959616 SCV004039361 likely pathogenic Proline dehydrogenase deficiency 2023-08-24 criteria provided, single submitter clinical testing Variant summary: PRODH c.930-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00017 in 155782 control chromosomes (gnomAD). To our knowledge, no occurrence of c.930-1G>C in individuals affected with Proline Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, and two as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001959616 SCV005916474 uncertain significance Proline dehydrogenase deficiency 2022-02-03 criteria provided, single submitter research

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