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

gnomAD frequency: 0.00005  dbSNP: rs372254398

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-03-29	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.
Counsyl	RCV000671284	SCV000796245	uncertain significance	Fanconi anemia complementation group A	2017-12-07	flagged submission	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV004742565	SCV005364568	pathogenic	FANCA-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The FANCA c.2639G>A variant is predicted to result in the amino acid substitution p.Arg880Gln. This variant has been reported in the compound heterozygous state in multiple individuals with Fanconi anemia (reported as c.2670G>A, Mankad et al. 2006. PubMed ID: 16397136; Castella et al. 2011. PubMed ID: 21273304; Kimble et al. 2017. PubMed ID: 29098742). In vitro functional studies demonstrated cellular mislocalization of the protein and impaired protein function which were restored by an in cis variant c.2896G>A (reported as 2927G>A, Mankad et al. 2006. PubMed ID: 16397136). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/555460/). This variant is interpreted as pathogenic.