VCV000013811.28 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 13811 Accession: VCV000013811.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119278181 (GRCh38) [ NCBI UCSC ] 11: 119148891 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 8, 2017	Oct 8, 2024	Dec 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005188.4:c.1111T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005179.2:p.Tyr371His	missense
NC_000011.10:g.119278181T>C
NC_000011.9:g.119148891T>C
NG_016808.1:g.76902T>C
LRG_608:g.76902T>C
LRG_608t1:c.1111T>C	LRG_608p1:p.Tyr371His
	P22681:p.Tyr371His

... more HGVS ... less HGVS

Protein change

Y371H

Other names

Canonical SPDI

NC_000011.10:119278180:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA123492 UniProtKB: P22681#VAR_071042 OMIM: 165360.0005 dbSNP: rs267606706 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CBL		No evidence available	No evidence available	GRCh38 GRCh37	1455	1609

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Noonan syndrome-like disorder with juvenile myelomonocytic leukemia	Pathogenic (1)	no assertion criteria provided	Oct 1, 2010	RCV000014822.25
Hematologic neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 26, 2014	RCV000437548.1
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 2, 2023	RCV000441724.15
RASopathy	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2023	RCV000691502.7
CBL-related disorder Juvenile myelomonocytic leukemia	Pathogenic (1)	criteria provided, single submitter	Dec 30, 2019	RCV001527385.5
Juvenile myelomonocytic leukemia	Pathogenic (1)	criteria provided, single submitter	Jul 7, 2023	RCV003315401.1
CBL-related disorder	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 27, 2023	RCV003387502.4
See cases	Pathogenic (1)	criteria provided, single submitter	Jul 8, 2022	RCV002274879.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003827495.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jul 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002562217.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Comment: ACMG categories: PS3,PM1,PM2,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Short stature (present) , Hypotonia (present) , Pes cavus (present) , Microcephaly (present) , Global developmental delay (present) , Low-set ears (present) , Short chin … (more) Short stature (present) , Hypotonia (present) , Pes cavus (present) , Microcephaly (present) , Global developmental delay (present) , Low-set ears (present) , Short chin (present) , Trigonocephaly (present) , Abnormal dentin morphology (present) (less) Age: 0-9 years Sex: male Tissue: blood
Pathogenic (Dec 30, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CBL-related disorder Juvenile myelomonocytic leukemia Affected status: no Allele origin: somatic	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001738403.1 First in ClinVar: Jun 25, 2021 Last updated: Jun 25, 2021	Comment: [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], … (more) [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]. (less)
Pathogenic (Dec 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CBL-related disorder Affected status: yes Allele origin: de novo	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV004239243.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CBL-related disorder Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099046.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PS2, PS3, PM1, PP3
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000518987.5 First in ClinVar: Mar 08, 2017 Last updated: Aug 18, 2023	Comment: 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, … (more) 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) (less)
Pathogenic (Feb 14, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927151.1 First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 Comment: Patient analyzed with Noonan Syndrome Panel
Pathogenic (Dec 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002103244.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (8) PubMed: 19571318‚ 20543203‚ 20694012‚ 24803665‚ 25283271‚ 25952305‚ 28414188‚ 32933826 Comment: PP1, PP3, PM1, PS2, PS3, PS4_moderate
Pathogenic (Nov 02, 2022)	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020) Method: clinical testing	Not provided Affected status: yes Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV003802791.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Publications: PubMed (4) PubMed: 25952305‚ 20543203‚ 20694012‚ 25283271 Comment: 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, … (more) 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. (less)
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile myelomonocytic leukemia Affected status: yes Allele origin: unknown	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004015268.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000819285.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20543203‚ 20694012‚ 25283271‚ 25952305‚ 28414188‚ 23696637 Comment: 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). … (more) 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. (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CBL-related disorder (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086423.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (6) PubMed: 20619386‚ 20694012‚ 25283271‚ 25358541‚ 25952305‚ 28414188 Comment: 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 … (more) 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 (less)
Pathogenic (Oct 01, 2010)	no assertion criteria provided Method: literature only	NOONAN SYNDROME-LIKE DISORDER WITH JUVENILE MYELOMONOCYTIC LEUKEMIA Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000035077.2 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2017	Publications: PubMed (3) PubMed: 20543203‚ 19571318‚ 20694012 Comment on evidence: In 3 unrelated patients with Noonan syndrome-like disorder and onset of juvenile myelomonocytic leukemia (JMML) in the first years of life (NSLL; 613563), Perez et … (more) In 3 unrelated patients with Noonan syndrome-like disorder and onset of juvenile myelomonocytic leukemia (JMML) in the first years of life (NSLL; 613563), Perez et al. (2010) identified a heterozygous germline 1111T-C transition in exon 8 of the CBL gene, resulting in a tyr371-to-his (Y371H) substitution. Phosphorylation of tyr371 is essential for the E3 activity of CBL and for its interaction with a number of signaling proteins. Leukemic cells from all patients showed loss of heterozygosity at chromosome 11q23, including the CBL gene. The patients all demonstrated subtle developmental defects, including dysmorphic facial features and poor growth, and 1 patient had developmental delay. Loh et al. (2009) identified a heterozygous germline Y371H mutation in 3 unrelated children with JMML, whereas leukemic cells from all 3 patients showed homozygosity for the mutation. Additional phenotypic features were not reported. Leukemic samples from 7 additional patients contained homozygous Y371H mutations. Germline/somatic mutation status of these patients was not reported. These findings indicated that tyr371 is a hotspot for mutations associated with JMML. Niemeyer et al. (2010) identified a heterozygous Y371H germline mutation in 7 of 21 unrelated patients with JMML. Leukemic cells from these patients showed homozygosity for the mutation, consistent with CBL functioning as a tumor suppressor gene. Two of the patients developed juvenile xanthogranulomas, and 3 had developmental delay. Family history was available from 2 patients. One had maternal relatives who died from progressive JMML and a maternal grandmother who had infantile leukemia that resolved spontaneously. The second had 2 male relatives who had died from JMML, one of whom developed small vessel vasculitis before his death. Leukemic cells from patients with the Y371H mutation showed GM-CSF hypersensitivity. In vitro studies in mouse cells with reduced Cbl expression showed that the mutant protein resulted in cytokine-independent proliferation and hypersensitivity to growth factors, associated with constitutive phosphorylation of several proteins. The mutant Y371H protein also showed a defect in E3 ligase function, supporting a role for tyr371 in maintaining the integrity of the alpha-helical structure of the linker region, which has a critical role in substrate specificity. Niemeyer et al. (2010) reported 3 additional heterozygous mutations affecting the tyr371 residue (see, e.g., 165360.0009). (less)
Pathogenic (Jun 20, 2024)	no assertion criteria provided Method: clinical testing	CBL-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362866.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Likely pathogenic (Dec 26, 2014)	no assertion criteria provided Method: literature only	Hematologic neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000505199.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 23696637 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000264033:c.1111T>C
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Comment:

[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].

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A child with juvenile myelomonocytic leukemia possessing a concurrent germline CBL mutation and a NF1 variant of uncertain significance: A rare case with a common problem in the era of high-throughput sequencing.	Wang WH	Journal of the Formosan Medical Association = Taiwan yi zhi	2021	PMID: 32933826
A case of splenomegaly in CBL syndrome.	Coe RR	European journal of medical genetics	2017	PMID: 28414188
Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations.	Martinelli S	Human mutation	2015	PMID: 25952305
Hydrops, fetal pleural effusions and chylothorax in three patients with CBL mutations.	Bülow L	American journal of medical genetics. Part A	2015	PMID: 25358541
Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder.	Hyakuna N	Pediatric blood & cancer	2015	PMID: 25283271
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.	Kiel C	Molecular systems biology	2014	PMID: 24803665
CBL linker region and RING finger mutations lead to enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via elevated levels of JAK2 and LYN.	Javadi M	The Journal of biological chemistry	2013	PMID: 23696637
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.	Niemeyer CM	Nature genetics	2010	PMID: 20694012
Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.	Martinelli S	American journal of human genetics	2010	PMID: 20619386
Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.	Pérez B	Journal of medical genetics	2010	PMID: 20543203
Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.	Loh ML	Blood	2009	PMID: 19571318
http://docm.genome.wustl.edu/variants/ENST00000264033:c.1111T>C	-	-	-	-
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Text-mined citations for rs267606706 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267606706 ...