ClinVar Miner

Submissions for variant NM_018328.4(MBD5):c.2978A>C (p.Gln993Pro) (rs761395486)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000719624 SCV000850493 likely benign History of neurodevelopmental disorder 2017-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
GeneDx RCV000490057 SCV000577408 uncertain significance not specified 2017-03-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MBD5 gene. The Q993P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q993P variant is observed in 8/11,558 (0.07%) alleles from individuals of Latino background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q993P 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 in mammals; however, Proline is observed at this position in evolution. Additionally, to our knowledge, only loss-of-function pathogenic variants in MBD5 have been published in association with epilepsy. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000226063 SCV000290459 uncertain significance Mental retardation, autosomal dominant 1 2018-08-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 993 of the MBD5 protein (p.Gln993Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs761395486, ExAC 0.07%). This variant has not been reported in the literature in individuals with MBD5-related disease. ClinVar contains an entry for this variant (Variation ID: 241285). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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