Submissions for variant NM_001378120.1(MBD5):c.205A>G (p.Ile69Val)

gnomAD frequency: 0.00001  dbSNP: rs749163361

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767156	SCV000241670	uncertain significance	not provided	2014-06-06	criteria provided, single submitter	clinical testing	p.Ile69Val (ATT>GTT): c.205 A>G in exon 7 of the MBD5 gene (NM_018328.4) The I69V 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. However, the I69V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved with Valine observed at this position in multiple species, and in silico analysis predicts this variant likely does not alter the protein structure/function. To our knowledge, only deletions and frameshift mutations in MBD5 have been published in association with epilepsy. The variant is found in EPILEPSY panel(s).
Genetic Services Laboratory, University of Chicago	RCV000188066	SCV000595706	likely benign	not specified	2017-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000188066	SCV004021156	uncertain significance	not specified	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: MBD5 c.205A>G (p.Ile69Val) results in a conservative amino acid change located in the methyl-CpG-DNA binding domain (IPR001739) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250988 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.205A>G in individuals affected with MBD5 Associated Neurodevelopmental Disorder and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765195	SCV004649433	uncertain significance	Intellectual disability, autosomal dominant 1	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 69 of the MBD5 protein (p.Ile69Val). This variant is present in population databases (rs749163361, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MBD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 206057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.