Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000658234 | SCV000780005 | uncertain significance | not provided | 2018-05-14 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MED12 gene. The I1387V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1387V variant is observed in 1/19138 (0.01%) alleles from individuals of South Asian background (Lek et al., 2016). The I1387V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV003596486 | SCV002271995 | uncertain significance | FG syndrome | 2023-09-29 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with MED12-related conditions. ClinVar contains an entry for this variant (Variation ID: 546370). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1387 of the MED12 protein (p.Ile1387Val). This variant is present in population databases (no rsID available, gnomAD 0.005%). |
| Ambry Genetics | RCV002331288 | SCV002630386 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2021-09-30 | criteria provided, single submitter | clinical testing | The p.I1387V variant (also known as c.4159A>G), located in coding exon 30 of the MED12 gene, results from an A to G substitution at nucleotide position 4159. The isoleucine at codon 1387 is replaced by valine, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/203658) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.005% (1/19061) of South Asian alleles. This amino acid position is conserved. In addition, this alteration 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. |
| Fulgent Genetics, |
RCV002507144 | SCV002814794 | uncertain significance | X-linked intellectual disability with marfanoid habitus; FG syndrome 1; Cholestasis-pigmentary retinopathy-cleft palate syndrome; Blepharophimosis - intellectual disability syndrome, MKB type | 2022-04-25 | criteria provided, single submitter | clinical testing |