ClinVar Miner

Submissions for variant NM_005120.3(MED12):c.568A>G (p.Ile190Val) (rs374780236)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121332 SCV000250615 uncertain significance not specified 2014-10-09 criteria provided, single submitter clinical testing p.Ile190Val (ATC>GTC): c.568 A>G in exon 5 of the MED12 gene (NM_005120.2) The I190V variant of unknown significance in the MED12 gene has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The I190V variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. However, the I190V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with MED12-related disorders, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD
Invitae RCV000633692 SCV000754959 uncertain significance FG syndrome 1 2019-08-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 190 of the MED12 protein (p.Ile190Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs374780236, ExAC 0.01%). This variant has not been reported in the literature in individuals with MED12-related disease. ClinVar contains an entry for this variant (Variation ID: 134638). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ITMI RCV000121332 SCV000085506 not provided not specified 2013-09-19 no assertion provided reference population

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