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

gnomAD frequency: 0.00002  dbSNP: rs267606708

Total submissions: 13

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816470	SCV000956980	pathogenic	RASopathy	2025-01-30	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBL protein function with a positive predictive value of 95%. 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.
Baylor Genetics	RCV001705593	SCV005049298	pathogenic	CBL-related disorder	2024-01-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004558248	SCV005049413	pathogenic	Juvenile myelomonocytic leukemia	2024-01-20	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001705593	SCV005398926	likely pathogenic	CBL-related disorder	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant negative is a likely mechanism of disease (PMID: 20619386, 20694012). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Germline CBL pathogenic variants are associated with phenotypic heterogeneity and variable expressivity (PMID: 25952305). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Pathogenic variants cluster in the linker region and RING finger domain (PMID: 25952305). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg420Leu) and p.(Arg420Pro) have both been once classified as a variant of unknown significance in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic/likely pathogenic six times in ClinVar, and has been reported in the literature in an individual diagnosed with Noonan syndrome-like disorder (PMID: 20619386, 22190897). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. p.(Arg420Gln) mutants were expressed in vitro. Compared to wild-type cells, mutants showed impaired EGFR ubiquitylation and increased RAS-MAPK signalling (PMID: 20619389, 25178484). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV001705593	SCV000035076	pathogenic	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
PreventionGenetics, part of Exact Sciences	RCV001705593	SCV005364971	likely pathogenic	CBL-related disorder	2024-06-16	no assertion criteria provided	clinical testing	The CBL c.1259G>A variant is predicted to result in the amino acid substitution p.Arg420Gln. This variant has been reported in an individual with acute myeloid leukemia (AML) (Sargin et al. 2007. PubMed ID: 17446348), and in a family with Noonan syndrome-like phenotype (Martinelli et al. 2010. PubMed ID: 20619386). This variant alters the conserved residue located in the RING finger domain which is a known mutational hot spot in myeloid malignancies. Functional studies showed that this variant causes aberrant ubiquitylation and trafficking of EGFR (Martinelli et al. 2010. PubMed ID: 20619386; Brand et al. 2014. PubMed ID: 25178484; Kiel et al. 2014. PubMed ID: 24803665). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD. In summary, this variant is interpreted as likely pathogenic.