ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3349A>G (p.Arg1117Gly) (rs149277003)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206698 SCV000259800 pathogenic Fanconi anemia 2017-07-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1117 of the FANCA protein (p.Arg1117Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases at a very low frequency (rs149277003, <0.01%) and has been reported in multiple patients affected with Fanconi anemia (PMID: 9371798, 22778927). Experimental studies have shown that this missense change causes disruption of several aspects of FANCA function in vitro (PMID: 24349332, 10373536, 11739169). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000254722 SCV000322263 pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing The R1117G variant in the FANCA gene has been reported previously in association with Fanconi anemia when in trans with another disease-causing variant (Levran et al., 1997; Gille et al., 2012). The R1117G variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1117G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Functional studies indicate that the R1117G 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). A missense variant in the same residue (R1117T) has been reported in the compound heterozygous state in a patient with Fanconi anemia (Yagasaki et al., 2004). We interpret R1117G as a pathogenic variant.
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.
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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