ClinVar Genomic variation as it relates to human health

Variant summary: PYCR1 c.797G>A (p.Arg266Gln) results in a conservative amino acid change located in the Pyrroline-5-carboxylate reductase, dimerisation domain (IPR029036) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant is located in the exonic splice region that alters the last nucleotide of exon 6 adjacent to the canonical splice donor site. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping of exon 6 (Guernsey_2009). The variant allele was found at a frequency of 7.7e-05 in 247824 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PYCR1 causing Cutis Laxa - PYCR1 Related (7.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.797G>A has been reported in the literature in multiple individuals affected with autosomal recessive PYCR1 Related Cutis Laxa (example, Guernsey_2009, Dimopoulou_2013, Reversade_2009, Rahmati_2015, Kariminejad_2017). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Observed in 21/279,222 (0.0075%) alleles in large population cohorts (gnomAD); RNA studies demonstrate homozygous individuals have a single smaller RNA band due to skipping of exon 6 and premature termination of the open reading frame, and heterozygous carriers have a mixture of RNA with normal and skipped products (Guernsey et al., 2009); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; 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: 21431621, 18304158, 19648921, 19576563, 28294978, 26516448, 22052856, 24035636, 31589614)

Across four different studies, the PYCR1 c.797G>A (p.Arg266Gln) variant was observed in a total of 11 individuals with cutis laxa, including eight homozygotes, two compound heterozygotes, and one proband of unknown zygosity (Reversade et al. 2009, Guernsey et al. 2009, Dimopoulou et al. 2013; Rahmati et al 2015). Family studies confirmed segregation of the p.Arg266Gln variant in a homozygous state with the disease phenotype. Guernsey et al. (2009) also determined the p.Arg266Gln missense variant results in an aberrant splice product which skips exon 6, deleting a conserved functional domain of the protein and generating a frameshift in the downstream exons leading to premature termination. The variant occurs at a highly conserved residue. The highest reported allele frequency was 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Arg266Gln variant is classified as pathogenic for autosomal recessive cutis laxa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 266 of the PYCR1 protein (p.Arg266Gln). This variant is present in population databases (rs121918374, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive cutis laxa (PMID: 19576563, 19648921). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13190). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.