ClinVar Miner

Submissions for variant NM_018328.4(MBD5):c.3389T>C (p.Ile1130Thr) (rs748142226)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522914 SCV000621067 uncertain significance not specified 2017-09-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MBD5 gene. The I1130T variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I1130T variant is observed in 1/66738 (0.0015%) alleles from individuals of Europeanbackground, in large population cohorts (Lek et al., 2016). The I1130T 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, only loss-of-function pathogenic variants in MBD5 have been published in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000823751 SCV000964621 uncertain significance Mental retardation, autosomal dominant 1 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1130 of the MBD5 protein (p.Ile1130Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs748142226, ExAC 0.001%). This variant has not been reported in the literature in individuals with MBD5-related disease. ClinVar contains an entry for this variant (Variation ID: 452274). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, 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.

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