ClinVar Miner

Submissions for variant NM_000135.2(FANCA):c.3788_3790delTCT (p.Phe1263del) (rs397507553)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231918 SCV000283566 pathogenic Fanconi anemia 2019-01-07 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 38 of the FANCA mRNA (c.3788_3790delTCT). This leads to the deletion of 1 amino acid residue in the FANCA protein (p.Phe1263del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507553, ExAC 0.03%). This is a common pathogenic variant for Fanconi anemia (FA) and has been reported as homozygous or compound heterozygous with other pathogenic variants in numerous FA patients. It is particularly common in Brazil and other populations of Caucasian or Latin origin (PMID: 15643609, 9371798, 21273304, 21659346). Experimental studies have shown that this sequence change alters nuclear localization of FANCA protein and impairs the function of FANCA in vitro (PMID: 21273304). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000485336 SCV000565881 pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing The c.3788_3790delTCT pathogenic variant in the FANCA gene has been reported previously either in the homozygous state or in combination with another FANCA variant in multiple unrelated individuals with Fanconi anemia (Levran et al., 1997; Castella et al., 2011; De Rocco et al., 2014). The c.3788_3790delTCT variant causes an in-frame deletion of one amino acid, Phenylalanine 1263, denoted p.Phe1263del. This amino acid deletion occurs at a position that is conserved across species. Functional studies demonstrated that c.3788_3790delTCT is associated with impaired FANCA function (Adachi et al., 2002). The c.3788_3790delTCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3788_3790delTCT as a pathogenic variant.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000231918 SCV000996088 pathogenic Fanconi anemia 2017-12-08 criteria provided, single submitter clinical testing This inframe deletion of a single amino acid has been reported as a homozygous and compound heterozygous change in individuals with Fanconi Anemia from ethnically diverse populations (PMID: 9371798, 21273304, 20301575). The highest allele frequency in the ExAC and gnomAD population databases is 0.03% with no reported homozygotes. Based on the available evidence, c.3788_3790delTCT (p. Phe1263del) is classified as pathogenic.
GeneReviews RCV000033896 SCV000057804 pathologic Fanconi anemia, complementation group A 2011-02-10 no assertion criteria provided curation Converted during submission to Pathogenic.
ITMI RCV000120945 SCV000085113 not provided not specified 2013-09-19 no assertion provided reference population
Counsyl RCV000033896 SCV000792032 pathogenic Fanconi anemia, complementation group A 2017-06-05 no assertion criteria provided clinical testing
OMIM RCV000033896 SCV000886138 pathogenic Fanconi anemia, complementation group A 2019-02-14 no assertion criteria provided literature only

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