ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.189+1G>A (rs891323617)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674205 SCV000799503 likely pathogenic Fanconi anemia, complementation group A 2018-04-23 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000674205 SCV000898675 likely pathogenic Fanconi anemia, complementation group A 2018-03-13 criteria provided, single submitter clinical testing FANCA NM_000135.3 exon 2 c.189+1G>A: This variant has not been reported in the literature but is present in 1/14984 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/-1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Mathew 2006 PMID:16998502). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000996416 SCV001151106 likely pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Invitae RCV001377209 SCV001574481 likely pathogenic Fanconi anemia 2020-02-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the FANCA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 557994). 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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