Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000196030 | SCV000255041 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-09-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 368 of the RET protein (p.Arg368His). This variant is present in population databases (rs199529397, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216712). 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 | RCV002453728 | SCV002740200 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-23 | criteria provided, single submitter | clinical testing | The p.R368H variant (also known as c.1103G>A), located in coding exon 6 of the RET gene, results from a G to A substitution at nucleotide position 1103. The arginine at codon 368 is replaced by histidine, an amino acid with highly similar properties. 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 data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in association with MEN2 based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. |
| Fulgent Genetics, |
RCV002478711 | SCV002792737 | uncertain significance | Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A | 2024-01-05 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004528988 | SCV004106373 | uncertain significance | RET-related disorder | 2023-06-24 | criteria provided, single submitter | clinical testing | The RET c.1103G>A variant is predicted to result in the amino acid substitution p.Arg368His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43604518-G-A). In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/216712/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Baylor Genetics | RCV003462336 | SCV004206711 | uncertain significance | Hirschsprung disease, susceptibility to, 1 | 2023-06-27 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000196030 | SCV005430317 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-06-11 | criteria provided, single submitter | clinical testing |