ClinVar Miner

Submissions for variant NM_001113378.2(FANCI):c.2507A>G (p.Asn836Ser) (rs933284199)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463193 SCV000547836 uncertain significance Fanconi anemia 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 836 of the FANCI protein (p.Asn836Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCI-related disease. ClinVar contains an entry for this variant (Variation ID: 408253). 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 serine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV001121010 SCV001279543 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001121010 SCV002011146 uncertain significance Fanconi anemia, complementation group I 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821273 SCV002064729 uncertain significance not specified 2021-04-16 criteria provided, single submitter clinical testing 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 0.0068% (dbSNP rs933284199). The p.Asn836Ser 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.Asn836Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Based on in silico splice prediction programs, this sequence change likely affects normal splicing of the FANCI gene, however functional studies have not been performed to prove this conclusively. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn836Ser change remains unknown at this time.

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