ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.248A>G (p.Tyr83Cys) (rs140992397)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206718 SCV000261532 uncertain significance Fanconi anemia 2018-02-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 83 of the FANCC protein (p.Tyr83Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs140992397, ExAC 0.01%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 220742). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000221187 SCV000279408 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted FANCC c.248A>G at the cDNA level, p.Tyr83Cys (Y83C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FANCC Tyr83Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RED domain (Gordon 2000). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether FANCC Tyr83Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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