Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000420005 | SCV000535676 | uncertain significance | not provided | 2016-12-20 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MED12 gene. The R91L variant 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 6,100 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 R91L 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 only amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. |
| Invitae | RCV003766456 | SCV001487222 | uncertain significance | FG syndrome | 2020-08-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with leucine at codon 91 of the MED12 protein (p.Arg91Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MED12-related conditions. ClinVar contains an entry for this variant (Variation ID: 392410). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MED12 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. |
| Duke University Health System Sequencing Clinic, |
RCV003223406 | SCV003918911 | uncertain significance | Blepharophimosis - intellectual disability syndrome, MKB type | 2023-04-20 | criteria provided, single submitter | research |