ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3349A>G (p.Arg1117Gly)

gnomAD frequency: 0.00006  dbSNP: rs149277003
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000206698 SCV000259800 pathogenic Fanconi anemia 2024-08-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1117 of the FANCA protein (p.Arg1117Gly). This variant is present in population databases (rs149277003, gnomAD 0.006%). This missense change has been observed in individuals with Fanconi anemia (PMID: 9371798, 22778927). ClinVar contains an entry for this variant (Variation ID: 219752). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects FANCA function (PMID: 10373536, 11739169, 24349332). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000254722 SCV000322263 pathogenic not provided 2022-09-29 criteria provided, single submitter clinical testing Published functional studies indicate that the variant allows FANCA mutant protein to bind FANCG in the cytoplasm but prevents translocation and accumulation in the nucleus, thereby blocking downstream events in the FA pathway (Garcia-Higuera et al., 2000; Yagasaki et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22778927, 10373536, 24349332, 11739169, 11050007, 30057198, 16084127, 9371798, 31970404, 28678401)
Johns Hopkins Genomics, Johns Hopkins University RCV000665865 SCV001762383 pathogenic Fanconi anemia complementation group A 2021-06-21 criteria provided, single submitter clinical testing FANCA c.3349A>G has been identified in multiple individuals with Fanconi anemia. This FANCA variant (rs149277003) is rare (<0.1%) in a large population dataset (gnomAD: 6/193422 total alleles; 0.003%; no homozygotes) and has been reported in ClinVar (Variation ID: 219752). Functional studies have suggested that p.Arg1117Gly affects multiple aspects of FANCA function including cellular localization and in vitro single strand annealing and strand exchange. We consider FANCA c.3349A>G to be pathogenic.
Revvity Omics, Revvity RCV000665865 SCV002024570 likely pathogenic Fanconi anemia complementation group A 2019-01-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000665865 SCV004196030 likely pathogenic Fanconi anemia complementation group A 2024-03-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000665865 SCV005642630 likely pathogenic Fanconi anemia complementation group A 2024-06-04 criteria provided, single submitter clinical testing
Counsyl RCV000665865 SCV000790056 likely pathogenic Fanconi anemia complementation group A 2017-03-14 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000665865 SCV001426115 pathogenic Fanconi anemia complementation group A 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter, Sue Richards.
Natera, Inc. RCV000665865 SCV001462880 pathogenic Fanconi anemia complementation group A 2020-09-16 no assertion criteria provided clinical testing

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