ClinVar Miner

Submissions for variant NM_001113378.2(FANCI):c.3896G>T (p.Arg1299Leu) (rs138663330)

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Total submissions: 4
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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 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1299 of the FANCI protein (p.Arg1299Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs138663330, ExAC 0.007%). This variant has not been reported in the literature in individuals 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 RCV000312524 SCV002011140 uncertain significance Fanconi anemia, complementation group I 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.

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