Submissions for variant NM_005188.4(CBL):c.1111T>C (p.Tyr371His)

gnomAD frequency: 0.00001  dbSNP: rs267606706

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691502	SCV000819285	pathogenic	RASopathy	2024-10-21	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). 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: 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 (IGM) Clinical Laboratory, Nationwide Children's Hospital	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, Mayo Clinic	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, University Hospital Muenster	RCV002274879	SCV002562217	pathogenic	See cases	2022-07-08	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PM2,PP3,PP5
Illumina Laboratory Services, Illumina	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, Revvity	RCV000441724	SCV003827495	pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	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, Greenwood Genetic Center	RCV003387502	SCV004099046	pathogenic	CBL-related disorder	2023-08-16	criteria provided, single submitter	clinical testing	PS2, PS3, PM1, PP3
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV003387502	SCV004239243	pathogenic	CBL-related disorder	2023-12-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003387502	SCV005086423	pathogenic	CBL-related disorder	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 pathogenic CBL variants are associated with variable phenotype (PMID: 25952305). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a moderate amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants, adjacent to the Prok-RING 4 domain (DECIPHER; PMIDs: 25358541, 25952305). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories (ClinVar). It has been reported in multiple individuals with Noonan syndrome or Noonan-like features with or without haematology anomalies. and confirmed to be de novo in the several probands (PMIDs: 25283271, 25952305, 28414188). In addition, this variant has been shown to be heterozygous in the germline tissue and homozygous in the somatic tissue (reviewed by PMID: 25952305). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000014822	SCV000035077	pathogenic	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia	2010-10-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003387502	SCV005362866	pathogenic	CBL-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The CBL c.1111T>C variant is predicted to result in the amino acid substitution p.Tyr371His. This variant has been reported as a heterozygous germline variant in patients with juvenile myelomonocytic leukemia (JMML) (Pathak et al. 2015. PubMed ID: 25939664), in patients with Noonan syndrome-like disorder with or without JMML (Perez et al. 2010. PubMed ID: 20543203; Neimeyer et al. 2010. PubMed ID: 20694012), and in unaffected family members of patients with JMML (Perez et al. 2010. PubMed ID: 20543203; Pathak et al. 2015. PubMed ID: 25939664), suggesting that this variant is incompletely penetrant. In patients with JMML, analysis of leukemia cells showed a somatically acquired loss of heterozygosity of chromosome 11q23, containing the CBL (Loh et al. 2009. PubMed ID: 19571318; Perez et al. 2010. PubMed ID: 20543203). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. In addition, other missense variants at this same amino acid have also been reported as pathogenic (p.Tyr371Asp, p.Tyr371Cys, p.Tyr371Asn, and p.Tyr371Ser) (Loh et al. 2009. PubMed ID: 19571318). Based on this evidence, we interpret this variant as pathogenic.