ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.974C>T (p.Ala325Val) (rs367618818)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115365 SCV000149274 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing This variant is denoted FANCC c.974C>T at the cDNA level, p.Ala325Val (A325V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FANCC Ala325Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region interacting with Hsp70 (Gordon & Buchwald 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 Ala325Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630831 SCV000751799 uncertain significance Fanconi anemia 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 325 of the FANCC protein (p.Ala325Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs367618818, ExAC 0.04%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 127551). 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: "Possibly 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.

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