ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1039A>T (p.Arg347Ter) (rs1555605532)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520821 SCV000618092 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1039A>T at the cDNA level and p.Arg347Ter (R347X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (AGA>TGA), and is predicted to cause loss of normal protein function through protein truncation as it results in the loss of 30 amino acids at the end of the protein. Furthermore, the truncation would remove the nuclear localization signal (French 2003). However, due to the location of the newly created nonsense codon near the end of the gene in exon 9, the transcript is not expected to undergo nonsense-mediated decay and could therefore encode a truncated protein that retains some normal function. This variant has not, to our knowledge, been reported in the literature. RAD51C Arg347Ter was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on the currently available information, we consider RAD51C Arg347Ter to be a variant of uncertain significance.
Invitae RCV000648241 SCV000770055 likely pathogenic Fanconi anemia, complementation group O 2017-09-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RAD51C gene (p.Arg347*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 29 amino acids of the RAD51C protein. 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. While the effects of this particular sequence change on RAD51C function has not been tested, the C-terminal region of RAD51C is known to contain a nuclear localization signal. Experimental studies have shown that deletion of the last 11 amino acid residues leads to cellular mislocalization of the RAD51C protein, as well as reduced mitomycin C resistance compared to the wild-type protein (PMID: 12966089). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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