ClinVar Miner

Submissions for variant NM_018062.3(FANCL):c.1051_1052delAG (p.Ser351Phefs) (rs750871999)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624824 SCV000742582 uncertain significance Inborn genetic diseases 2017-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae RCV000469469 SCV000547808 likely pathogenic Fanconi anemia 2018-04-23 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 13 of the FANCL mRNA (c.1051_1052delAG), causing a frameshift at codon 351. This creates a premature translational stop signal in the penultimate exon of the FANCL mRNA (p.Ser351Phefs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acids of the FANCL protein. This variant is present in population databases (rs765729177, ExAC 0.05%) but has not been reported in the literature in individuals with a FANCL-related disease. Experimental studies have not been performed to test the effect of this variant on FANCL protein function or stability. However, this variant partially deletes the PHD/RING finger domain, including 2 of the 8 conserved zinc-coordinating cysteine residues that are essential for ubiquitin ligase activity (PMID: 24389026, 19111657, 17938197). This domain is necessary for FANCL interaction with Ube2t and Ube2w, and subsequent monoubiquitination of FANCD2 (PMID: 12973351, 17938197, 19111657). For these reasons, this variant has been classified as Likely Pathogenic.

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