Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000474895 | SCV000547740 | pathogenic | Fanconi anemia | 2019-02-28 | criteria provided, single submitter | clinical testing | This variant affects a highly conserved nucleotide within the consensus splice site of intron 7. The majority of introns (75%) have a G at this position (PMID: 9536098). This variant is present in population databases (rs759877008, ExAC 0.01%). This variant occurs with 3 different pathogenic variants (p.E1254X, p.E383RfsX32, p.R853X) in FANCA in three unrelated individuals with Fanconi anemia (PMID: 8896563, 10094191, 21273304, 19423727). While it is unknown in two of these cases if the two variants are on the same or opposite chromosomes, these observations suggest that the c.709+5G>A substitution may contribute to the cause of disease. This variant is also known as 740+5G>A or IVS7+5G>A in the literature. Nucleotide substitutions at the +5 position of the intron are relatively common causes of aberrant splicing (PMID: 17576681). Experimental studies have shown that this intronic change affects the normal donor splice site and results in the use of a cryptic splice site 30 nucleotides downstream in intron 7, thereby leading to the insertion of 10 novel amino acids in the FANCA protein. This mutant FANCA protein was shown to be defective in restoring FANCD2 monoubiquitination in FANCA-deficient lymphoblasts (PMID: 19423727). For these reasons, this variant has been classified as Pathogenic. |
| Counsyl | RCV000673202 | SCV000798378 | likely pathogenic | Fanconi anemia, complementation group A | 2018-03-07 | criteria provided, single submitter | clinical testing |