Submissions for variant NM_001018115.3(FANCD2):c.2444G>A (p.Arg815Gln)

gnomAD frequency: 0.00004  dbSNP: rs766567785

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234321	SCV000291157	pathogenic	Fanconi anemia	2023-12-21	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 815 of the FANCD2 protein (p.Arg815Gln). This variant is present in population databases (rs766567785, gnomAD 0.05%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 17436244, 27041517). 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: 241735). 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%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001194923	SCV002022347	pathogenic	Fanconi anemia complementation group D2	2019-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000234321	SCV003923231	pathogenic	Fanconi anemia	2023-03-02	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.2444G>A (p.Arg815Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251202 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCD2 causing Fanconi Anemia (0.00013 vs 0.00048), allowing no conclusion about variant significance. c.2444G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Fanconi Anemia and was shown to segregate with disease within at least one family (Kalb_2007, Esmail Nia_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001194923	SCV004196713	pathogenic	Fanconi anemia complementation group D2	2024-03-27	criteria provided, single submitter	clinical testing
GeneDx	RCV004701326	SCV005201756	pathogenic	not provided	2024-09-22	criteria provided, single submitter	clinical testing	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: 27795557, 31589614, Chan2021[article], 30713837, 17436244, 32191290, 34308104, 35417938, 35725860, 27041517)
Leiden Open Variation Database	RCV001194923	SCV001364788	pathogenic	Fanconi anemia complementation group D2	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
PreventionGenetics, part of Exact Sciences	RCV004754365	SCV005359718	pathogenic	FANCD2-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The FANCD2 c.2444G>A variant is predicted to result in the amino acid substitution p.Arg815Gln. This variant has been reported in the homozygous or compound heterozygous state in several patients with Fanconi anemia (Kalb et al 2007. PubMed ID: 17436244; Esmail et al. 2016. PubMed ID: 27041517; Deniskin et al. 2018. PubMed ID: 30713837). This variant has also been reported along with a second variant in FANCD2 in two individuals with osteosarcoma (eTable 5, Mirabello et al. 2020. PubMed ID: 32191290). This variant is reported in 0.058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.