ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3517_3519TGG[1] (p.Trp1174del) (rs1555536446)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540300 SCV000626188 pathogenic Fanconi anemia 2018-09-21 criteria provided, single submitter clinical testing This variant, c.3520_3522delTGG, results in the deletion of 1 amino acid of the FANCA protein (p.Trp1174del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous and on the opposite chromosome (in trans) from other  pathogenic variants in individuals affected with Fanconi anemia (FA) (PMID: 9371789, 17924555, 23613520, 25703136). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 456115). Experimental studies have shown that this sequence change severely impairs the function of the FANCA protein in vitro. Specifically, this sequence change reduces FANCA phosphorylation, nuclear localization, interaction with other FA proteins, and the downstream ubiquitination of FANCD2 (PMID: 12444097).  In addition, a functional study to identify FA complementation groups using FA-associated correction of G2/M arrest showed that this variant falls into complementation group A (PMID: 16084127). For these reasons, this variant has been classified as Pathogenic.

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