ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1009C>T (p.Leu337Phe) (rs587779899)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115340 SCV000149249 uncertain significance not provided 2016-10-10 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1009C>T at the cDNA level, p.Leu337Phe (L337F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Leu337Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. FANCC Leu337Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in Hsp70 binding domain (Gordon 2000). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether FANCC Leu337Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000197177 SCV000254249 uncertain significance Fanconi anemia 2015-05-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 337 of the FANCC protein (p.Leu337Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant has not been published in the literature and is present in population databases (no rs ID, <0.01%). ClinVar contains an entry for this variant (RCV000115340). 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"). However, the phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In summary, this is a rare missense change with uncertain impact on protein function. Although there is no indication that this variant causes disease, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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