ClinVar Miner

Submissions for variant NM_018328.4(MBD5):c.1327G>T (p.Val443Leu) (rs137977565)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485500 SCV000570942 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing The V443L variant in the MBD5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V443L variant was not observed in approximately 6500 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 V443L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We therefore interpret V443L as a variant of uncertain significance.
Invitae RCV000538625 SCV000645779 uncertain significance Mental retardation, autosomal dominant 1 2017-05-24 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 443 of the MBD5 protein (p.Val443Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs137977565, ExAC 0.002%). This variant has not been reported in the literature in individuals with a MBD5-related disease. ClinVar contains an entry for this variant (Variation ID: 421660). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant has uncertain impact on MBD5 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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