ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.521G>A (p.Arg174Gln) (rs755283850)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466061 SCV000549955 uncertain significance Fanconi anemia 2018-08-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 174 of the FANCC protein (p.Arg174Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. It also falls at the last nucleotide of exon 6 of the FANCC coding sequence. This variant is present in population databases (rs755283850, ExAC 0.009%) but has not been reported in the literature in individuals with a FANCC-related disease. 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 glutamine 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001023751 SCV001185669 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing Insufficient evidence

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