ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.1445C>G (p.Pro482Arg)

gnomAD frequency: 0.00006  dbSNP: rs768676657
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000816328 SCV000956829 uncertain significance Fanconi anemia 2022-10-05 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the FANCA protein (p.Pro482Arg). This variant is present in population databases (rs768676657, gnomAD 0.005%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 31102422). ClinVar contains an entry for this variant (Variation ID: 659338). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271589 SCV002555741 uncertain significance not specified 2022-06-08 criteria provided, single submitter clinical testing Variant summary: FANCA c.1445C>G (p.Pro482Arg) results in a non-conservative amino acid change located in the Fanconi anaemia group A protein, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1445C>G has been reported in the literature in settings of multigene testing in individuals affected with pediatric acute lymphoblastic leukemia (example Zhang_2015, de Smith_2019). However, to our knowledge the variant has not been reported in individuals affected with Fanconi Anemia and no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002478900 SCV002774563 uncertain significance not provided 2021-08-09 criteria provided, single submitter clinical testing
Natera, Inc. RCV001274149 SCV001457953 uncertain significance Fanconi anemia complementation group A 2020-09-16 no assertion criteria provided clinical testing

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