ClinVar Miner

Submissions for variant NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)

gnomAD frequency: 0.00002  dbSNP: rs267606708
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414703 SCV000491156 pathogenic not provided 2023-07-21 criteria provided, single submitter clinical testing Functional studies demonstrate that R420Q impairs epidermal growth factor receptor (EGFR) ubiquitylation and degredation, and the R420Q-containing RING domain is not able to function as an E3 ubiquitin ligase (PMID: 25178484, 17446348); This variant is associated with the following publications: (PMID: 19734451, 24803665, 17446348, 21768087, 20619386, 25952305, 32054657, 31751678, 32855275, 34026204, 35033063, 33627783, 33512474, 35967575, 22246246, 35008940, 33318624, 33372952, 34906245, 35583390, 25178484, 22315494)
Invitae RCV000816470 SCV000956980 pathogenic RASopathy 2023-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the CBL protein (p.Arg420Gln). This variant is present in population databases (rs267606708, gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 20619386, 33318624). ClinVar contains an entry for this variant (Variation ID: 13810). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CBL protein function. Experimental studies have shown that this missense change affects CBL function (PMID: 17446348, 20619386, 22246246, 25178484, 33627783). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001705593 SCV001934399 likely pathogenic CBL-related disorder 2021-01-26 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001705593 SCV002061816 likely pathogenic CBL-related disorder 2021-12-28 criteria provided, single submitter clinical testing PS3, PM2
Revvity Omics, Revvity RCV000414703 SCV003824973 likely pathogenic not provided 2021-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000816470 SCV003922954 pathogenic RASopathy 2023-03-07 criteria provided, single submitter clinical testing Variant summary: CBL c.1259G>A (p.Arg420Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the RING-type Zinc finger (IPR001841) of the encoded protein sequence. Four 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 251418 control chromosomes. c.1259G>A has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (e.g. Digilio_2010, Kauffmann_2021, Martinelli_2010). These data indicate that the variant is likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function, finding that the variant inhibits CBL ubiquitin ligase function and EGFR trafficking (Sargin_2007, Martinelli_2010, Brand_2014). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000014821 SCV000035076 pathogenic Fragile site 11b; CBL-related disorder 2010-08-13 no assertion criteria provided literature only
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257538 SCV001434364 pathogenic Rhabdomyosarcoma 2020-09-01 no assertion criteria provided provider interpretation
Molecular Diagnostics Laboratory, University of Rochester Medical Center RCV003447475 SCV004175185 likely pathogenic Myeloproliferative disorder no assertion criteria provided provider interpretation

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