ClinVar Miner

Submissions for variant NM_018328.4(MBD5):c.801C>G (p.His267Gln) (rs747135508)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498279 SCV000589378 uncertain significance not provided 2017-06-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MBD5 gene. The H267Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H267Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H267Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, 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 RCV001061510 SCV001226255 uncertain significance Mental retardation, autosomal dominant 1 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 267 of the MBD5 protein (p.His267Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MBD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 431841). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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