ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.1776+1G>A (rs756140957)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523348 SCV000618803 likely pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing The c.1776+1G>A variant in the FANCA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 19. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1776+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1776+1G>A as a likely pathogenic variant.
Invitae RCV000685268 SCV000812744 likely pathogenic Fanconi anemia 2019-09-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the FANCA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs756140957, ExAC 0.009%). This variant has been observed in combination with another FANCA variant in an individual affected with Fanconi anemia (PMID: 29098742). ClinVar contains an entry for this variant (Variation ID: 450248). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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