ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.679A>G (p.Ile227Val) (rs864622550)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204753 SCV000261084 uncertain significance Fanconi anemia 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 227 of the FANCC protein (p.Ile227Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. 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 valine amino acid residue is also 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 is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482871 SCV000566593 uncertain significance not provided 2015-05-15 criteria provided, single submitter clinical testing This variant is denoted FANCC c.679A>G at the cDNA level, p.Ile227Val (I227V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Ile227Val 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 Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. FANCC Ile227Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in region of interaction with Hsp70 and GRP94 (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 Ile227Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001025655 SCV001187893 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-15 criteria provided, single submitter clinical testing Insufficient evidence

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