ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1159T>C (p.Cys387Arg) (rs1064793837)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483173 SCV000567154 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1159T>C at the cDNA level, p.Cys387Arg (C387R) at the protein level, and results in the change of a Cysteine to an Arginine (TGC>CGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Cys387Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Cys387Arg occurs at a position that is not conserved and is located in the region of interaction with Hsp70 (Gordon 2000). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether FANCC Cys387Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000806505 SCV000946509 uncertain significance Fanconi anemia 2018-07-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 387 of the FANCC protein (p.Cys387Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 419389). 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 and their clinical significance is uncertain. 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.

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