ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2353C>G (p.Arg785Gly) (rs781254854)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478565 SCV000564525 likely pathogenic not provided 2014-07-07 criteria provided, single submitter clinical testing This variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The R785G variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R785G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is moderately conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in this residue and a nearby residue (R785C, S795R) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000478565 SCV001237181 uncertain significance not provided 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 785 of the ABCA4 protein (p.Arg785Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs781254854, ExAC 0.1%). This variant has not been reported in the literature in individuals with ABCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 417985). 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 disruptive, but 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.

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