ClinVar Miner

Submissions for variant NM_005188.3(CBL):c.202C>T (p.Arg68Trp) (rs730880429)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157854 SCV000207784 uncertain significance not provided 2014-03-18 criteria provided, single submitter clinical testing This variant is denoted p.Arg68Trp at the protein level, c.202 C>T at the cDNA level, and results in the change of an Arginine to a Tryptophan (CGG>TGG) in exon 2 of the CBL gene (NM_005188.2). The R68W missense change in the CBL gene has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. The R68W amino acid substitution is non-conservative with a positively charged and polar residue (Arg) being replaced by a neutral and non-polar residue (Trp). The residue at which this substitution occurs is conserved in the protein. The R68W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, no other disease-causing mutations have been reported in the surrounding residues. Therefore, the R68W missense change is interpreted as a variant of unknown significance. This variant was observed to co-occur with a known pathogenic mutation, SOS1. The variant is found in NOONAN panel(s).
Invitae RCV000549374 SCV000659105 uncertain significance Rasopathy 2017-11-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 68 of the CBL protein (p.Arg68Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CBL-related disease. ClinVar contains an entry for this variant (Variation ID: 180811). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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