Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000413174 | SCV000492004 | uncertain significance | not specified | 2016-11-14 | criteria provided, single submitter | clinical testing | The V121I variant in the RET gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. 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 V121I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. However, a missense variant in nearby residue (T120T) has 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 V121I is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance. |
Ambry Genetics | RCV000563413 | SCV000674835 | likely benign | Hereditary cancer-predisposing syndrome | 2018-09-28 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Invitae | RCV001062267 | SCV001227054 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2022-11-04 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 121 of the RET protein (p.Val121Ile). This variant is present in population databases (rs770548816, gnomAD 0.008%). 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: 373412). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |