ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.626G>A (p.Arg209His) (rs587778327)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168381 SCV000219072 uncertain significance Fanconi anemia 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 209 of the FANCC protein (p.Arg209His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587778327, ExAC 0.03%) but has not been reported in the literature in individuals with a FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 188350). 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 variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482249 SCV000567486 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing This variant is denoted FANCC c.626G>A at the cDNA level, p.Arg209His (R209H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Arg209His was observed at an allele frequency of 0.03% (9/30,416) in individuals of South Asian ancestry in large population cohorts (Lek 2016). FANCC Arg209His is located within the region of interaction with Hsp70 and GRP94 (Gordon 2000). 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 Arg209His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001025063 SCV001187185 likely benign Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing Insufficient evidence

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