Submissions for variant NM_005188.4(CBL):c.1298C>T (p.Pro433Leu)

gnomAD frequency: 0.00001  dbSNP: rs140627020

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157862	SCV000207792	uncertain significance	not provided	2020-09-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813407	SCV002060745	uncertain significance	Noonan syndrome and Noonan-related syndrome	2017-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850196	SCV002175507	uncertain significance	RASopathy	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 433 of the CBL protein (p.Pro433Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 180817). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBL protein function with a positive predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271423	SCV002556018	uncertain significance	not specified	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: CBL c.1298C>T (p.Pro433Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1298C>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004019905	SCV003543950	uncertain significance	Cardiovascular phenotype	2022-10-04	criteria provided, single submitter	clinical testing	The c.1298C>T (p.P433L) alteration is located in exon 9 (coding exon 9) of the CBL gene. This alteration results from a C to T substitution at nucleotide position 1298, causing the proline (P) at amino acid position 433 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004737248	SCV005356454	uncertain significance	CBL-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The CBL c.1298C>T variant is predicted to result in the amino acid substitution p.Pro433Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-119149290-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.