Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000546890 | SCV000626197 | pathogenic | Fanconi anemia | 2024-09-28 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 38 of the FANCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 29098742; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 456123). 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. |
Revvity Omics, |
RCV001783028 | SCV002022318 | pathogenic | Fanconi anemia complementation group A | 2019-02-12 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001783028 | SCV004196547 | pathogenic | Fanconi anemia complementation group A | 2024-03-26 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV003935400 | SCV004750129 | pathogenic | FANCA-related disorder | 2024-02-26 | no assertion criteria provided | clinical testing | The FANCA c.3828+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is predicted to abolish the consensus exon 38 splice donor site according to available splice prediction programs (Alamut Visual plus v1.6.1) and has been reported in a patient with Fanconi anemia who also harbored a large deletion of the FANCA gene presumably on the opposite chromosome (Kimble et al. 2018. PubMed ID: 29098742). A different variant affecting the same splice site, c.3828+1G>T has also been reported to cause FA (Castella et al. 2011. PubMed ID: 21273304) suggesting that disruption of the exon 38 splice donor site is not tolerated. This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/456123/). Variants that disrupt the consensus splice donor site in FANCA are expected to be pathogenic. This variant is interpreted as pathogenic. |