Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001001813 | SCV001159478 | uncertain significance | Hereditary pancreatitis | 2018-09-25 | criteria provided, single submitter | clinical testing | The CTRC c.356G>A; p.Arg119His variant (rs748221308), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with a low overall allele frequency of 0.003% (8/245982 alleles) in the Genome Aggregation Database. The arginine at codon 119 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious to protein structure/function. Additionally, this variant is located in the last nucleotide of exon 4 and may alter splicing by weakening the canonical donor site and creating a cryptic splice acceptor site (Alamut v.2.11). However, due to the lack of clinical and functional data, the significance of p.Arg119His is uncertain at this time. |
| Ambry Genetics | RCV001001813 | SCV001182140 | uncertain significance | Hereditary pancreatitis | 2023-09-14 | criteria provided, single submitter | clinical testing | The p.R119H variant (also known as c.356G>A), located in coding exon 4 of the CTRC gene, results from a G to A substitution at nucleotide position 356. The arginine at codon 119 is replaced by histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 4 and may have some effect on normal mRNA splicing. This alteration was detected once in a control from a study that sequenced pancreatic cancer susceptibility genes in a cohort of individuals with pancreatic cancer and control individuals (Tamura K et al. Proc. Natl. Acad. Sci. U.S.A., 2018 05;115:4767-4772). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001001813 | SCV001541047 | uncertain significance | Hereditary pancreatitis | 2023-09-05 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. ClinVar contains an entry for this variant (Variation ID: 811638). This variant has not been reported in the literature in individuals affected with CTRC-related conditions. This variant is present in population databases (rs748221308, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 119 of the CTRC protein (p.Arg119His). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. |
| Mayo Clinic Laboratories, |
RCV003480900 | SCV004227771 | uncertain significance | not provided | 2022-09-13 | criteria provided, single submitter | clinical testing |