ClinVar Miner

Submissions for variant NM_030973.4(MED25):c.1210G>A (p.Gly404Arg)

gnomAD frequency: 0.00001  dbSNP: rs1213960931
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000704021 SCV000832954 uncertain significance Charcot-Marie-Tooth disease type 2 2021-08-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 404 of the MED25 protein (p.Gly404Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MED25-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987674 SCV004803744 uncertain significance not specified 2024-01-24 criteria provided, single submitter clinical testing Variant summary: MED25 c.1210G>A (p.Gly404Arg) results in a non-conservative amino acid change located in the Mediator complex, subunit Med25, PTOV domain (IPR021394) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.1210G>A in individuals affected with Congenital Cataract-Microcephaly Flammeus Simplex-Severe Intellectual Disability Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 580471). Based on the evidence outlined above, the variant was classified as uncertain significance.

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