ClinVar Miner

Submissions for variant NM_001113378.2(FANCI):c.1399G>A (p.Val467Ile) (rs199726965)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233977 SCV000285882 uncertain significance Fanconi anemia 2019-06-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 467 of the FANCI protein (p.Val467Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199726965, ExAC 0.03%). This variant has not been reported in the literature in individuals with FANCI-related disease. ClinVar contains an entry for this variant (Variation ID: 238308). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Illumina Laboratory Services,Illumina RCV000763987 SCV000394195 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.
Fulgent Genetics,Fulgent Genetics RCV000763987 SCV000894938 uncertain significance Fanconi anemia, complementation group I 2018-10-31 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818580 SCV002064674 uncertain significance not specified 2020-01-13 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCI gene demonstrated a sequence change, c.1399G>A, in exon 15 that results in an amino acid change, p.Val467Ile. 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 frequency of 0.04% in European populations (dbSNP rs199726965). The p.Val467Ile change affects a moderately conserved amino acid residue located in a domain of the FANCI protein that is not known to be functional. The p.Val467Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val467Ile change remains unknown at this time.

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