Submissions for variant NM_001018115.3(FANCD2):c.2204G>A (p.Arg735Gln)

gnomAD frequency: 0.00001  dbSNP: rs755975980

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001092963	SCV001249720	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001325183	SCV001516162	uncertain significance	Fanconi anemia	2023-07-26	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 872482). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 23285130). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs755975980, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 735 of the FANCD2 protein (p.Arg735Gln).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265942	SCV002547623	uncertain significance	not specified	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.2204G>A (p.Arg735Gln) 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 1.6e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2204G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Fanconi Anemia (example, Knies_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.