ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.121G>C (p.Val41Leu) (rs879254131)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235241 SCV000293599 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.121G>C at the cDNA level, p.Val41Leu (V41L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Val41Leu 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 Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. RAD51C Val41Leu occurs at a position that is not conserved and is located in the region required for Holliday junction resolution activity (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 Val41Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567552 SCV000667105 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-16 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000648254 SCV000770068 uncertain significance Fanconi anemia, complementation group O 2019-02-24 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 41 of the RAD51C protein (p.Val41Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. 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: 246163). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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