ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.2607G>C (p.Gln869His) (rs1555545583)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000527790 SCV000626170 uncertain significance Fanconi anemia 2017-04-07 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 869 of the FANCA protein (p.Gln869His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCA-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Gln869Pro) has been reported in individuals affected with Fanconi anemia in the literature (PMID: 15643609) and in the Leiden Open-source Variation Database (PMID: 21520333), however, in some of these individuals, a second FANCA variant was not identified. In addition, an experimental study demonstrates that this variant may disrupt FANCA protein complex formation with FANCB and FANCL (PMID: 16720839). This suggests that the glutamine residue is may be critical for FANCA protein function. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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