ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.2639G>A (p.Arg880Gln)

gnomAD frequency: 0.00005  dbSNP: rs372254398
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671284 SCV000796245 uncertain significance Fanconi anemia complementation group A 2017-12-07 criteria provided, single submitter clinical testing
Invitae RCV000803258 SCV000943121 pathogenic Fanconi anemia 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 880 of the FANCA protein (p.Arg880Gln). This variant is present in population databases (rs372254398, gnomAD 0.01%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 16397136, 19367192, 21273304, 29098742; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555460). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FANCA function (PMID: 16397136, 21273304). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000671284 SCV001142708 likely pathogenic Fanconi anemia complementation group A 2019-05-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000803258 SCV002511385 pathogenic Fanconi anemia 2022-04-24 criteria provided, single submitter clinical testing Variant summary: FANCA c.2639G>A (p.Arg880Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251458 control chromosomes. c.2639G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Fanconi Anemia (example, Mankad_2006, Moghrabi_2009, Castella_2011, Kimble_2018). These data indicate that the variant is very likely to be associated with disease. At-least one publication reports experimental evidence that this variant results in primarily cytoplasmic expression and reduced function of the mutant FANCA protein (Mankad_2006). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as Likely Pathogenic/Pathogenic (n=5) (VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4 RCV000803258 SCV002534962 likely pathogenic Fanconi anemia 2022-01-06 criteria provided, single submitter curation
Baylor Genetics RCV000671284 SCV004195985 pathogenic Fanconi anemia complementation group A 2023-10-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003478396 SCV004221974 pathogenic not provided 2022-05-20 criteria provided, single submitter clinical testing In the published literature, the variant has been reported in individuals with Fanconi Anemia (PMID: 29904161 (2019), 29098742 (2018), 21273304 (2011), 19367192 (2009), 16397136 (2006)). This variant has also been shown to have a deleterious effect on FANCA protein function (PMID: 16397136 (2006)). The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
OMIM RCV000671284 SCV000886137 pathogenic Fanconi anemia complementation group A 2022-01-11 no assertion criteria provided literature only
Leiden Open Variation Database RCV000671284 SCV001425971 pathogenic Fanconi anemia complementation group A 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Sue Richards.
Natera, Inc. RCV000671284 SCV001452861 likely pathogenic Fanconi anemia complementation group A 2020-09-16 no assertion criteria provided clinical testing

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