Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001063719 | SCV001228578 | pathogenic | Fanconi anemia | 2022-05-05 | criteria provided, single submitter | clinical testing | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FANCC protein in which other variant(s) (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8882868, 24584348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 857945). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 14 of the FANCC gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001585965 | SCV001821246 | likely pathogenic | Fanconi anemia complementation group C | 2021-08-13 | criteria provided, single submitter | clinical testing | Variant summary: FANCC c.1533+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251152 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1533+1G>T in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV002402446 | SCV002706671 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-06 | criteria provided, single submitter | clinical testing | The c.1533+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 13 of the FANCC gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is insufficient at this time (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |