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

gnomAD frequency: 0.00013  dbSNP: rs755922289

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000630961	SCV000751937	pathogenic	Fanconi anemia	2024-01-25	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 951 of the FANCA protein (p.Arg951Gln). This variant also falls at the last nucleotide of exon 29, which is part of the consensus splice site for this exon. This variant is present in population databases (rs755922289, gnomAD 0.01%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 17924555, 22778927, 24584348). 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: 526433). 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: 12697994). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts the p.Arg951 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17924555, 22778927, 24349332, 24584348, 26799702). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000666705	SCV000791048	likely pathogenic	Fanconi anemia complementation group A	2017-04-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001569733	SCV001793868	pathogenic	not provided	2022-10-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: retention in the cytoplasm preventing cells from repairing DNA (Bottega et al,. 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24584348, 28102861, 25525159, 17924555, 12697994, 11063725, 22778927, 32054657, 28973083, 29269525)
CeGaT Center for Human Genetics Tuebingen	RCV001569733	SCV001961640	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001569733	SCV002070494	likely pathogenic	not provided	2020-02-14	criteria provided, single submitter	clinical testing	The sequence change, c.2852G>A, in exon 29 results in an amino acid change, p.Arg951Gln. This sequence change has been described in the gnomAD database with a low population frequency of 0.01% in European sub-population (dbSNP rs755922289). The p.Arg951Gln change affects a highly conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. The p.Arg951Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Arg951Gln change has been reported in several individuals with Fanconi anemia (PMID: 17924555, 22778927, 24584348). In one of these individuals, this sequence change was shown to be in trans with a different pathogenic sequence change (PMID: 24584348). A different pathogenic sequence change affecting the same amino acid residue, p.Arg951Trp, has also been described in patients with FANCA-related disorders (PMID: 22778927, 17924555, 24584348, 26799702, 17924555, 24584348, 24349332). Functional studies have demonstrated disrupted protein function in the presence of the p.Arg951Gln change (PMID: 12697994). These collective evidences indicate that this sequence change is likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000666705	SCV002804623	pathogenic	Fanconi anemia complementation group A	2022-04-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666705	SCV004195995	pathogenic	Fanconi anemia complementation group A	2023-10-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000666705	SCV001452857	pathogenic	Fanconi anemia complementation group A	2020-09-16	no assertion criteria provided	clinical testing
GeneReviews	RCV000666705	SCV001737414	not provided	Fanconi anemia complementation group A		no assertion provided	literature only	Associated with slower hematologic disease progression
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001569733	SCV001809681	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001569733	SCV001959168	pathogenic	not provided		no assertion criteria provided	clinical testing