ClinVar Miner

Submissions for variant NM_005188.3(CBL):c.1871T>C (p.Leu624Ser) (rs150550899)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033363 SCV000057268 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing This variant is denoted as p.Leu624Ser at the protein level, c.1871 T>C at the cDNA level, and results in the change of a Leucine for a Serine (TTG>TCG) in exon 11 of the CBL gene (NM_005188.2). The L624S missense change in the CBL gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The L624S amino acid substitution is non-conservative with a non-polar residue (Leu) being replaced by a polar residue (Ser). The residue at which this substitution occurs is highly evolutionarily conserved in the protein. However, no missense mutations have been reported in the CBL gene beyond codon Arginine 420 (Martinelli et al., 2010). Therefore, the L624S missense change in the CBL gene is interpreted to be a variant of unknown significance. The variant is found in NOONAN panel(s).
Invitae RCV000459030 SCV000543493 uncertain significance Rasopathy 2018-06-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 624 of the CBL protein (p.Leu624Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs150550899, ExAC 0.05%) but has not been reported in the literature in individuals with a CBL-related disease. ClinVar contains an entry for this variant (Variation ID: 40415). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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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