ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1297C>T (p.Arg433Cys) (rs369684405)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115341 SCV000149250 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1297C>T at the cDNA level, p.Arg433Cys (R433C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FANCC Arg433Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether FANCC Arg433Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206060 SCV000259762 uncertain significance Fanconi anemia 2015-08-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 433 of the FANCC protein (p.Arg433Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs369684405, 0.01%) but has not been published in the literature. ClinVar contains an entry for this variant (RCV000115341). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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