ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.2852G>A (p.Arg951Gln) (rs755922289)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666705 SCV000791048 likely pathogenic Fanconi anemia, complementation group A 2017-04-24 criteria provided, single submitter clinical testing
Invitae RCV000630961 SCV000751937 pathogenic Fanconi anemia 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 951 of the FANCA protein (p.Arg951Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 29 of the FANCA coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is present in population databases (rs755922289, ExAC 0.01%). This variant has been reported in several individuals affected with Fanconi anemia (PMID: 17924555, 22778927, 24584348), and has been shown to be on the opposite chromosome (in trans) from a different pathogenic variant in one of those individuals (PMID: 24584348). These findings are consistent with autosomal recessive inheritance, and suggest that this variant contributes to disease. Experimental studies have shown that this missense disrupts the normal functioning of the FANCA protein (PMID: 12697994). A different missense substitution at this codon (p.p.Arg951Trp) has been determined to be pathogenic (PMID: 22778927, 17924555, 24584348, 26799702, 17924555, 24584348, 24349332). This suggests that the arginine residue is critical for FANCA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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