ClinVar Genomic variation as it relates to human health

The PRSS1 c.364C>G; p.Arg122Gly variant (rs111033568), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 440202). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.365G>A; p.Arg122His, c.364C>T; p.Arg122Cys) have been reported in individuals with hereditary pancreatitis and are considered pathogenic (Chen 2009, Nemeth 2014). The arginine at codon 122 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.559). Given the lack of clinical and functional data, the clinical significance of the p.Arg122Gly variant is uncertain at this time. References: Chen JM and Ferec C. Chronic pancreatitis: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2009;10:63-87. Nemeth BC and Sahin-Toth M. Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2014 Mar;306(6):G466-73.

This variant disrupts the p.Arg122 amino acid residue in PRSS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8841182, 11097832, 11748242, 19453252). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces arginine, a(n) basic and polar amino acid, with glycine, a(n) neutral and non-polar amino acid, at codon 122 of the PRSS1 protein (p.Arg122Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRSS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 440202). 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.

The p.R122G variant (also known as c.364C>G), located in coding exon 3 of the PRSS1 gene, results from a C to G substitution at nucleotide position 364. The arginine at codon 122 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.