ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3400_3402TTC[1] (p.Phe1135del) (rs786204246)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168439 SCV000219136 pathogenic Fanconi anemia 2016-07-14 criteria provided, single submitter clinical testing This sequence change deletes three nucleotides from exon 34 of the FANCA mRNA (c.3403_3405delTTC). This leads to the deletion of one amino acid residue in the FANCA protein (p.Phe1135del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs786204246, ExAC no frequency). This sequence change was reported in an individual affected with Fanconi anemia (FA). Whether this variant segregates with disease remains uncertain (PMID: 10521298). Additionally, this variant has been observed in trans with a pathogenic mutation in an affected individual in the Invitae database. ClinVar contains an entry for this variant (Variation ID: 188384). Experimental studies have shown that this sequence change severely impairs the function of FANCA in vitro. Specifically, this sequence change reduces FANCA phosphorylation, nuclear localization, interaction with other FA proteins, and the downstream ubiquitination of FANCD2 (PMID: 12444097). For these reasons, this variant has been classified as Pathogenic.

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