ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.709+5G>A (rs759877008)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474895 SCV000547740 pathogenic Fanconi anemia 2020-04-19 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
Institute of Human Genetics, University of Leipzig Medical Center RCV000673202 SCV001429202 pathogenic Fanconi anemia, complementation group A 2020-01-03 criteria provided, single submitter clinical testing
OMIM RCV000673202 SCV000224033 pathogenic Fanconi anemia, complementation group A 2009-07-02 no assertion criteria provided literature only
Leiden Open Variation Database RCV000673202 SCV001425625 pathogenic Fanconi anemia, complementation group A 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Johan den Dunnen.
Natera, Inc. RCV000673202 SCV001459006 pathogenic Fanconi anemia, complementation group A 2020-09-16 no assertion criteria provided clinical testing

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