ClinVar Miner

Submissions for variant NM_005188.3(CBL):c.1754G>A (p.Arg585His) (rs727504640)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157865 SCV000207795 uncertain significance not provided 2018-03-26 criteria provided, single submitter clinical testing The R585H variant in the CBL gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R585H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R585H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R585H as a variant of uncertain significance.
Invitae RCV000546705 SCV000659099 uncertain significance Rasopathy 2017-02-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 585 of the CBL protein (p.Arg585His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs727504640, ExAC 0.003%) but has not been reported in the literature in individuals with a CBL-related disease. ClinVar contains an entry for this variant (Variation ID: 180820). 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 histidine 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. In summary, this variant is a rare missense change that is not predicted to affect 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.

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