ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.745A>G (p.Ser249Gly) (rs539583288)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484872 SCV000568875 uncertain significance not provided 2018-04-24 criteria provided, single submitter clinical testing This variant is denoted FANCC c.745A>G at the cDNA level, p.Ser249Gly (S249G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Ser249Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the regions of interaction with GRP94 and Hsp70 (Gordon 2000). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether FANCC Ser249Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000803094 SCV000942953 uncertain significance Fanconi anemia 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 249 of the FANCC protein (p.Ser249Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs539583288, ExAC 0.03%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 420182). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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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