ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1595G>A (p.Arg532Lys) (rs55939573)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199976 SCV000254256 uncertain significance Fanconi anemia 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 532 of the FANCC protein (p.Arg532Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs55939573, ExAC 0.07%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 216285). 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: "Probably 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 RCV000520121 SCV000618137 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1595G>A at the cDNA level, p.Arg532Lys (R532K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FANCC Arg532Lys was observed at an allele frequency of 0.09% (16/17,244) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the cdc2 binding domain (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 Arg532Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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