ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1634A>G (p.Lys545Arg) (rs571668582)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214884 SCV000279675 uncertain significance not provided 2015-12-08 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1634A>G at the cDNA level, p.Lys545Arg (K545R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Lys545Arg was not observed at a significant allele frequency in 1000 Genomes. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. FANCC Lys545Arg occurs at a position that is not conserved and is located in a region responsible for cdc2 binding (Gordon and Buchwald). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Lys545Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543270 SCV000626240 uncertain significance Fanconi anemia 2017-02-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 545 of the FANCC protein (p.Lys545Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs571668582, 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: 234672). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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