ClinVar Miner

Submissions for variant NM_022725.3(FANCF):c.2T>G (p.Met1Arg) (rs745495865)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462200 SCV000547707 likely pathogenic Fanconi anemia 2018-08-17 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the FANCF mRNA. While it is expected to result in an absent or disrupted protein product, an alternate in-frame methionine downstream of the initiator codon is located at codon 145, which could potentially rescue translational initiation. This variant is present in population databases (rs745495865, ExAC 0.009%). This variant has been observed as homozygous in an individual with microcytic anemia and thrombocytopenia, cafe-au-lait spots, and a positive chromosome breakage test result (Invitae). ClinVar contains an entry for this variant (Variation ID: 408144). Experimental studies evaluating the function of a deletion mutant lacking the highly conserved first 15 amino acids of FANCF showed that the mutant protein was not able to complement MMC hypersensitivity in FANCF-deficient cells, and disrupted the interaction with the FANCC/FANCE sub-complex (PMID: 15262960). These results indicate that the first 15 amino acid residues are critical for FANCF protein function. For these reasons, this variant has been classified as Likely Pathogenic.

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