ClinVar Miner

Submissions for variant NM_001378120.1(MBD5):c.3680C>T (p.Ala1227Val)

gnomAD frequency: 0.00003  dbSNP: rs773522192
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188105 SCV000241711 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing p.Ala994Val (GCG>GTG): c.2981 C>T in exon 11 of the MBD5 gene (NM_018328.4) The A994V 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 A994V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals but is not conserved in more distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. 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 CHILD-EPIV2-1 panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV001364510 SCV001560663 uncertain significance Intellectual disability, autosomal dominant 1 2024-12-17 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 994 of the MBD5 protein (p.Ala994Val). This variant is present in population databases (rs773522192, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MBD5-related conditions (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 206091). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MBD5 protein function with a negative predictive value of 80%. 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.
Revvity Omics, Revvity RCV001364510 SCV003808320 uncertain significance Intellectual disability, autosomal dominant 1 2022-03-02 criteria provided, single submitter clinical testing

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