Submissions for variant NM_001113378.2(FANCI):c.3896G>T (p.Arg1299Leu)

gnomAD frequency: 0.00038  dbSNP: rs138663330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000312524	SCV000394230	uncertain significance	Fanconi anemia complementation group I	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001213730	SCV001385379	uncertain significance	Fanconi anemia	2022-06-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1299 of the FANCI protein (p.Arg1299Leu). This variant is present in population databases (rs138663330, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FANCI-related conditions. ClinVar contains an entry for this variant (Variation ID: 317301). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237822	SCV002011140	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820938	SCV002066769	uncertain significance	not specified	2021-01-05	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCI gene demonstrated a sequence change, c.3896G>T, in exon 37 that results in an amino acid change, p.Arg1299Leu. This sequence change does not appear to have been previously described in patients with FANCI-related disorders and has been described in the gnomAD database with a low population frequency of 0.020% in the non- Finnish European subpopulation (dbSNP rs138663330). The p.Arg1299Leu change affects a poorly conserved amino acid residue located in a domain of the FANCI protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1299Leu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1299Leu change remains unknown at this time.
Sema4, Sema4	RCV001213730	SCV002529852	uncertain significance	Fanconi anemia	2021-08-24	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000312524	SCV003833930	uncertain significance	Fanconi anemia complementation group I	2020-08-17	criteria provided, single submitter	clinical testing