ClinVar Miner

Submissions for variant NM_004629.1(FANCG):c.1747G>T (p.Glu583Ter) (rs786204205)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168294 SCV000218972 likely pathogenic Fanconi anemia 2017-07-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FANCG gene (p.Glu583*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 40 amino acids of the FANCG protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with a likely pathogenic FANCG de novo missense variant (p.Pro385Thr) in an individual affected with Fanconi anemia (PMID: 23613520). ClinVar contains an entry for this variant (Variation ID: 188303). This variant is expected to delete the last 40 amino acids (residues Glu583-Leu622) of the FANCG protein. Although functional studies have not been done for this particular variant, experimental studies have shown that loss of the most C-terminal 37 amino acids of the FANCG protein impairs its binding to the FANCA protein, resulting in the inability to complement mitomycin C (MMC) sensitivity (PMID: 10567393, 10961856). While the mechanism of FANCG-FANCA binding is still being resolved, and additional sequences may be involved (PMID: 10567393, 10652215, 14697762, 20450923), the data suggests that deletion of this region of the FANCG protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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