ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.851C>T (p.Ala284Val) (rs201281511)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658080 SCV000779851 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing The A284V variant in the FANCC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A284V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A284V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is located in a critical functional domain (Gordon and Buchwald, 2000). We interpret A284V as a variant of uncertain significance.
Invitae RCV000814395 SCV000954804 uncertain significance Fanconi anemia 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 284 of the FANCC protein (p.Ala284Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs201281511, ExAC 0.009%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 546233). 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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