ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1628C>A (p.Ser543Ter) (rs867319477)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409524 SCV000485726 likely pathogenic Fanconi anemia, complementation group C 2016-02-03 criteria provided, single submitter clinical testing
GeneDx RCV000657699 SCV000779448 likely pathogenic not provided 2016-10-10 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1628C>A at the cDNA level and p.Ser543Ter (S543X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Even though this truncation occurs near the end of the gene and nonsense-mediated decay is not expected to occur, it is significant since the last 49 amino acids are no longer translated. Furthermore, the truncation would disrupt the region of interaction with cdc2 (Gordon 2000). Although this variant has not, to our knowledge, been reported in the literature, we consider it to be likely pathogenic.
Invitae RCV001059596 SCV001224223 pathogenic Fanconi anemia 2019-10-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FANCC gene (p.Ser543*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acids of the FANCC protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 370412). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminus of the FANCC protein. Other variant(s) that disrupt this region (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8882868, 24584348). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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