ClinVar Miner

Submissions for variant NM_001113378.2(FANCI):c.3907G>A (p.Glu1303Lys) (rs544848412)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV001117650 SCV001275859 uncertain significance Fanconi anemia, complementation group I 2018-01-12 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 RCV001320447 SCV001511233 uncertain significance Fanconi anemia 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1303 of the FANCI protein (p.Glu1303Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs544848412, ExAC 0.1%). This variant has not been reported in the literature in individuals with FANCI-related conditions. ClinVar contains an entry for this variant (Variation ID: 885822). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genetic Services Laboratory, University of Chicago RCV001819827 SCV002070409 uncertain significance not specified 2021-12-15 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCI gene demonstrated a sequence change, c.3907G>A, in exon 37 that results in an amino acid change, p.Glu1303Lys. This sequence change has been described in the gnomAD database with a frequency of 0.095% in the East Asian subpopulation (dbSNP rs544848412). The p.Glu1303Lys change affects a poorly conserved amino acid residue located in a domain of the FANCI protein that is not known to be functional. The p.Glu1303Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with FANCI-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu1303Lys change remains unknown at this time.

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