Submissions for variant NM_018328.4(MBD5):c.3539A>T (p.Asp1180Val) (rs752035001)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188117	SCV000241724	uncertain significance	not provided	2014-09-26	criteria provided, single submitter	clinical testing	p.Asp1180Val (D1180V) GAT>GTT: c.3539 A>T in exon 12 of the MBD5 gene (NM_018328.4) The D1180V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 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 D1180V 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 through mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, only deletions and frameshift mutations 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 mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae	RCV000472716	SCV000545115	uncertain significance	Mental retardation, autosomal dominant 1	2018-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with valine at codon 1180 of the MBD5 protein (p.Asp1180Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs752035001, ExAC 0.04%). This variant has not been reported in the literature in individuals with MBD5-related disease. ClinVar contains an entry for this variant (Variation ID: 206103). 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.
Fulgent Genetics,Fulgent Genetics	RCV000472716	SCV000896828	uncertain significance	Mental retardation, autosomal dominant 1	2018-10-31	criteria provided, single submitter	clinical testing

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