ClinVar Miner

Submissions for variant NM_018328.4(MBD5):c.2903C>T (p.Ser968Leu) (rs200985982)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724687 SCV000225389 uncertain significance not provided 2015-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000724687 SCV000241710 uncertain significance not provided 2016-03-08 criteria provided, single submitter clinical testing The S968L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 S968L 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, only loss-of-function pathogenic variants 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 variant or a rare benign variant.
Invitae RCV000702921 SCV000831798 uncertain significance Mental retardation, autosomal dominant 1 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 968 of the MBD5 protein (p.Ser968Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs200985982, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MBD5-related conditions. ClinVar contains an entry for this variant (Variation ID: 193912). 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: "Not Available"; Align-GVGD: "Class C65"). 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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