ClinVar Miner

Submissions for variant NM_001113378.1(FANCI):c.2326A>G (p.Met776Val) (rs150544323)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522385 SCV000620835 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing The M776V variant in the FANCI gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M776V variant is observed in 17/10304 (0.16%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The M776V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M776V as a variant of uncertain significance.
Invitae RCV000699113 SCV000827809 uncertain significance Fanconi anemia 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 776 of the FANCI protein (p.Met776Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs150544323, ExAC 0.2%). This variant has not been reported in the literature in individuals with FANCI-related disease. ClinVar contains an entry for this variant (Variation ID: 452060). 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 tolerated, 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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