ClinVar Miner

Submissions for variant NM_006907.4(PYCR1):c.535G>A (p.Ala179Thr)

gnomAD frequency: 0.00004  dbSNP: rs139751598
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519424 SCV000616844 likely pathogenic not provided 2022-12-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19648921, 21834030, 23963297, 24035636, 30450527, 31589614)
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856791 SCV000999352 pathogenic Autosomal recessive cutis laxa type 2B criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001584233 SCV001821308 pathogenic Cutis laxa 2021-08-19 criteria provided, single submitter clinical testing Variant summary: PYCR1 c.535G>A (p.Ala179Thr) results in a non-conservative amino acid change located in the Pyrroline-5-carboxylate reductase, dimerisation domain (IPR029036) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 245914 control chromosomes. c.535G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with PYCR1 Related Cutis Laxa (example, Kouwenberg_2011, Reversade_2009, Dimopoulou_2013, Gardeitchik_2014) and as a compound heterozygous genotype in at-least one patient with features of non LMNA associated juvenile progeroid disorder (example, Lessel_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000519424 SCV002024776 likely pathogenic not provided 2021-12-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000519424 SCV002278833 likely pathogenic not provided 2024-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 179 of the PYCR1 protein (p.Ala179Thr). This variant is present in population databases (rs139751598, gnomAD 0.004%). This missense change has been observed in individual(s) with cutis laxa (PMID: 19648921, 21834030, 30450527). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 449091). 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 not expected to disrupt PYCR1 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV005018889 SCV005652837 likely pathogenic Autosomal recessive cutis laxa type 2B; PYCR1-related de Barsy syndrome 2024-04-27 criteria provided, single submitter clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV001291131 SCV001479507 likely pathogenic Wiedemann-Rautenstrauch-like progeroid syndrome no assertion criteria provided research

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