Total submissions: 10
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, |
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, |
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, |
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, |
RCV000671284 | SCV001452861 | likely pathogenic | Fanconi anemia complementation group A | 2020-09-16 | no assertion criteria provided | clinical testing |