rs111033568
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BS2_Supporting
The NM_002769.5(PRSS1):āc.364C>Gā(p.Arg122Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R122C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002769.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRSS1 | NM_002769.5 | c.364C>G | p.Arg122Gly | missense_variant | 3/5 | ENST00000311737.12 | NP_002760.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PRSS1 | ENST00000311737.12 | c.364C>G | p.Arg122Gly | missense_variant | 3/5 | 1 | NM_002769.5 | ENSP00000308720.7 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461878Hom.: 0 Cov.: 61 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74270
ClinVar
Submissions by phenotype
Hereditary pancreatitis Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 27, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 10, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at