ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.733C>T (p.Arg245Trp) (rs571548182)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204215 SCV000260057 uncertain significance Fanconi anemia 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 245 of the FANCC protein (p.Arg245Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs571548182, 0.006%) but has not been reported in the literature in individuals with a FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 219908). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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 RCV000487303 SCV000570676 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing This variant is denoted FANCC c.733C>T at the cDNA level, p.Arg245Trp (R245W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Arg245Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). FANCC Arg245Trp is located in the region of interaction with GRP94 and Hsp70 (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 Arg245Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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