ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3551G>C (p.Arg1184Pro) (rs147672303)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001094249 SCV000399823 uncertain significance Fanconi anemia, complementation group A 2018-01-13 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.
GeneDx RCV000484383 SCV000573678 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing The R1184P variant in the FANCA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1184P variant is observed in 20/58508 alleles (0.034%) alleles from individuals of European (Non-Finnish) background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1184P variant is a non-conservative amino acid substitution, which occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1184P as a variant of uncertain significance.
Invitae RCV000287104 SCV000626189 uncertain significance Fanconi anemia 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1184 of the FANCA protein (p.Arg1184Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs147672303, ExAC 0.03%) but has not been reported in the literature in individuals with a FANCA-related disease. ClinVar contains an entry for this variant (Variation ID: 321335). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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