ClinVar Miner

Submissions for variant NM_030973.3(MED25):c.316G>A (p.Gly106Arg) (rs535472885)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482797 SCV000571047 likely pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing The G106R variant in the MED25 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G106R variant was not observed in approximately 6500 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 G106R 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 across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G106R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV001238346 SCV001411150 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 106 of the MED25 protein (p.Gly106Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs535472885, ExAC 0.01%). This variant has not been reported in the literature in individuals with MED25-related conditions. ClinVar contains an entry for this variant (Variation ID: 421749). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV001249635 SCV001423602 likely pathogenic Charcot-Marie-Tooth disease type 2B2; Basel-Vanagaite-Smirin-Yosef syndrome 2019-01-07 criteria provided, single submitter clinical testing [ACMG/AMP: PM2, PM3, PP2, PM5] This alteration is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5].

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