Submissions for variant NM_001018115.3(FANCD2):c.904C>T (p.Arg302Trp)

gnomAD frequency: 0.00001  dbSNP: rs121917787

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000012820	SCV000891278	likely pathogenic	Fanconi anemia complementation group D2	2016-11-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809924	SCV000950107	pathogenic	Fanconi anemia	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 302 of the FANCD2 protein (p.Arg302Trp). This variant is present in population databases (rs121917787, gnomAD 0.002%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 11239453, 22720145, 25703294; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12040). 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 FANCD2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FANCD2 function (PMID: 11239453, 17308347, 22828868). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000012820	SCV002024586	likely pathogenic	Fanconi anemia complementation group D2	2019-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000012820	SCV004196720	pathogenic	Fanconi anemia complementation group D2	2024-02-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000012820	SCV005877133	pathogenic	Fanconi anemia complementation group D2	2024-09-30	criteria provided, single submitter	clinical testing	The FAND2 c.904C>T; p.Arg302Trp variant (rs121917787; ClinVar ID: 12040) is reported in the literature in several individuals affected with Fanconi anemia that carried a second pathogenic variant in trans (Ameziane 2012, Timmers 2001, Zhang 2016). The p.Arg302Trp variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.715). Consistent with predictions, functional analyses indicate the variant protein has reduced stability and impaired function (Nookala 2007, Sato 2012, Timmers 2001). Based on available information, this variant is considered to be pathogenic. References: Ameziane N et al. Diagnosis of fanconi anemia: mutation analysis by next-generation sequencing. Anemia. 2012;2012:132856. PMID: 22720145. Nookala RK et al. Insights into Fanconi Anaemia from the structure of human FANCE. Nucleic Acids Res. 2007;35(5):1638-48. PMID: 17308347. Sato K et al. Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair. EMBO J. 2012 Aug 29;31(17):3524-36. PMID: 22828868. Timmers C et al. Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell. 2001 Feb;7(2):241-8. PMID: 11239453. Zhang J et al. Utility of next-generation sequencing technologies for the efficient genetic resolution of haematological disorders. Clin Genet. 2016 Feb;89(2):163-72. PMID: 25703294.
OMIM	RCV000012820	SCV000033060	pathogenic	Fanconi anemia complementation group D2	2001-02-01	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000012820	SCV001364772	pathogenic	Fanconi anemia complementation group D2	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.