Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000441724 | SCV000518987 | pathogenic | not provided | 2023-08-02 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect (Niemeyer et al., 2010; Javadi et al., 2013).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20543203, 25952305, 27609087, 25283271, 19571318, 20694012, 23696637, 24803665, 27577878, 26911351, 28082680, 26676746, 28414188, 32933826, 20619386, 22315494) |
Invitae | RCV000691502 | SCV000819285 | pathogenic | RASopathy | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 371 of the CBL protein (p.Tyr371His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with juvenile myelomonocytic leukemia and Noonan-like syndrome (PMID: 20543203, 20694012, 25283271, 25952305, 28414188). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13811). 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 95%. Experimental studies have shown that this missense change affects CBL function (PMID: 20694012, 23696637). For these reasons, this variant has been classified as Pathogenic. |
Blueprint Genetics | RCV000441724 | SCV000927151 | pathogenic | not provided | 2017-02-14 | criteria provided, single submitter | clinical testing | |
Institute for Genomic Medicine |
RCV001527385 | SCV001738403 | pathogenic | Juvenile myelomonocytic leukemia; CBL-related disorder | 2019-12-30 | criteria provided, single submitter | clinical testing | [ACMG/AMP: PS2, PS3, PM1, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is predicted to be damaging by multiple functional prediction tools [PP3]. |
Mayo Clinic Laboratories, |
RCV000441724 | SCV002103244 | pathogenic | not provided | 2021-12-28 | criteria provided, single submitter | clinical testing | PP1, PP3, PM1, PS2, PS3, PS4_moderate |
Institute of Human Genetics, |
RCV002274879 | SCV002562217 | pathogenic | See cases | 2022-07-08 | criteria provided, single submitter | clinical testing | ACMG categories: PS3,PM1,PM2,PP3,PP5 |
Illumina Laboratory Services, |
RCV000441724 | SCV003802791 | pathogenic | not provided | 2022-11-02 | criteria provided, single submitter | clinical testing | The CBL c.1111T>C (p.Tyr371His) missense variant results in the substitution of tyrosine at amino acid 371 with histidine. Across a selection of the available literature, this variant has been identified in a heterozygous state in at least 13 individuals with Noonan syndrome-like disorder with or without juvenile monomyelocytic leukemia, including six individuals in which the variant was de novo (PMID: 20543203; PMID: 20694012; PMID: 25283271; PMID: 25952305). There are several instances in which the variant was inherited from a parent, however detailed phenotype is not provided (PMID: 20543203; PMID: 20694012). At least three other missense variants at the same residue have been reported in individuals with the condition (PMID: 20694012). The reported frequency of this allele in the Genome Aggregation Database is 0.000011 in the total population (version 2.1.1). Functional studies have demonstrated a gain-of-function effect for the c.1111T>C variant (PMID: 20694012). Based on the available evidence, the c.1111T>C (p.Tyr371His) variant is classified as pathogenic for Noonan syndrome-like disorder with or without juvenile monomyelocytic leukemia. |
Revvity Omics, |
RCV000441724 | SCV003827495 | pathogenic | not provided | 2022-10-21 | criteria provided, single submitter | clinical testing | |
KCCC/NGS Laboratory, |
RCV003315401 | SCV004015268 | pathogenic | Juvenile myelomonocytic leukemia | 2023-07-07 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with histidine at codon 371 of the CBL protein (p.Tyr371His). The tyrosine residue is highly conserved (PhyloP=7.65) .This variant is not present in population databases (GnomAD). This variant has been reported with CBL-Related Disorder, Hematopoietic and Lymphoid Cell Neoplasm and Hematopoietic and Lymphoid System Neoplasm in the following publications: (PMID: 20543203, 25952305, 27609087, 25283271, 19571318, 20694012, 23696637, 24803665, 27577878, 26911351, 28082680, 26676746, 28414188, 32933826). ClinVar contains an entry for this variant (Variation ID: 13811) from seven clinical lab after 2014 and all labs were classified this variant as pathogenic. |
Greenwood Genetic Center Diagnostic Laboratories, |
RCV003387502 | SCV004099046 | pathogenic | CBL-related disorder | 2023-08-16 | criteria provided, single submitter | clinical testing | PS2, PS3, PM1, PP3 |
Institute of Human Genetics, |
RCV003387502 | SCV004239243 | pathogenic | CBL-related disorder | 2023-12-27 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000014822 | SCV000035077 | pathogenic | Noonan syndrome-like disorder with juvenile myelomonocytic leukemia | 2010-10-01 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437548 | SCV000505199 | likely pathogenic | Hematologic neoplasm | 2014-12-26 | no assertion criteria provided | literature only |