ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.382G>C (p.Gly128Arg) (rs879254160)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236224 SCV000293686 uncertain significance not provided 2015-12-16 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.382G>C at the cDNA level, p.Gly128Arg (G128R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Gly128Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Gly128Arg occurs at a position that is conserved across species and is located in the ATP binding motif and region of interaction with RAD51B, RAD51D and XRCC3 (Miller 2004, Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51C Gly128Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000699264 SCV000827966 uncertain significance Fanconi anemia, complementation group O 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 128 of the RAD51C protein (p.Gly128Arg). 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 with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 246222). 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, but 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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