Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000425402 | SCV000521035 | uncertain significance | not provided | 2016-10-24 | criteria provided, single submitter | clinical testing | The R175C variant in the RET gene has previously been reported in at least one individual with Hirschsprung disease (Carter et al., 2002). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R175C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts R175C is probably damaging to the protein structure/function. Missense variants in nearby residues (F174S, R180Q, R180P) have been reported in the Human Gene Mutation Database in association with Hirschsprung disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether R175C is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV000461265 | SCV000543805 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the RET protein (p.Arg175Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hirschsprung's disease or cervical adenocarcinoma (PMID: 22648184, 26556299). ClinVar contains an entry for this variant (Variation ID: 381592). 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 disruptive. 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. |
| Ambry Genetics | RCV001023784 | SCV001185703 | uncertain significance | Hereditary cancer-predisposing syndrome | 2025-01-17 | criteria provided, single submitter | clinical testing | The p.R175C variant (also known as c.523C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide position 523. The arginine at codon 175 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in one individual with Hirschsprung disease (Carter TC et al. J. Hum. Genet., 2012 Aug;57:485-93). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| All of Us Research Program, |
RCV000461265 | SCV004817089 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-01-11 | criteria provided, single submitter | clinical testing |