VCV000045196.20 - ClinVar

NM_005188.4(CBL):c.1096-1G>C

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Functional data are available for this variant

Variant Details

Identifiers

NM_005188.4(CBL):c.1096-1G>C

Variation ID: 45196 Accession: VCV000045196.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119278165 (GRCh38) [ NCBI UCSC ] 11: 119148875 (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	Jan 31, 2015	Apr 13, 2025	Dec 17, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_005188.4:c.1096-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000011.10:g.119278165G>C
NC_000011.9:g.119148875G>C
NG_016808.1:g.76886G>C
LRG_608:g.76886G>C
LRG_608t1:c.1096-1G>C

... more HGVS ... less HGVS

Protein change

Other names

NM_005188.4:c.1096-1G>C

Canonical SPDI

NC_000011.10:119278164:G:C

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.

Links

dbSNP: rs397517076 ClinGen: CA135696 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	2097	2323

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	Pathogenic (1)	criteria provided, single submitter	Dec 6, 2012	RCV000038346.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 26, 2017	RCV000624342.3
Noonan syndrome-like disorder with juvenile myelomonocytic leukemia	Pathogenic (1)	criteria provided, single submitter	May 18, 2020	RCV001270818.5
RASopathy	Pathogenic (1)	criteria provided, single submitter	Dec 17, 2021	RCV001852803.5
CBL-related disorder Juvenile myelomonocytic leukemia	Likely pathogenic (1)	criteria provided, single submitter	Aug 12, 2021	RCV002482996.1

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Aug 12, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Juvenile myelomonocytic leukemia CBL-related disorder	Fulgent Genetics, Fulgent Genetics Accession: SCV002789062.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Dec 06, 2012) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Noonan syndrome	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062018.5 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Publications: PubMed (2) PubMed: 20694012‚ 19571318 Comment: show The 1096-1G>C variant in CBL has been reported in one individual with clinical f eatures of Noonan syndrome and juvenile myelomonocytic leukemia (JMML; Loh 2009, Niemeyer 2010). This variant was reported to be homozygous in a blood sample an d heterozygous in the germline. Studies have shown that the 1096-1G>A variant i mpacts splicing (Niemeyer 2010). In addition, this variant was not identified in either parent of this individual and therefore likely occurred de novo, assumin g that non-medical explanations including alternate paternity or undisclosed ado ption have been ruled out. This finding supports that this variant is disease ca using and responsible for Noonan-like syndrome and juvenile myelomonocytic leuke mia in this individual. In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Pathogenic (May 18, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Noonan syndrome-like disorder with juvenile myelomonocytic leukemia	Illumina Laboratory Services, Illumina Accession: SCV001451582.1 First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020	Publications: PubMed (6) PubMed: 18698078‚ 19571318‚ 20694012‚ 23823657‚ 25358541‚ 28589114 Comment: show The CBL c.1096-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in a heterozygous state in one child with juvenile myelomonocytic leukemia who also presented with cafÃ©-au-lait spots, juvenile xanthogranuloma, cryptorchidism, poor growth, developmental delay, and supraventricular tachycardia (Niemeyer et al. 2010). In addition, evaluation of non-germline cells in this child and two additional individuals showed the c.1096-1G>C variant present in a either a homozygous or heterozygous state (Loh et al. 2009; Niemeyer et al. 2010; Strullu et al. 2013). The c.1096-1G>C variant is located in intron 7. RT-PCR showed the presence of in-frame protein products lacking exon 8, which encompasses the functionally important RING finger domain (Abbas et al. 2008; Niemeyer et al. 2010). Additional splice site variants at the same genomic position with different base changes have also been described in individuals with RASopathy or Noonan-like phenotypes (Strullu et al. 2013; Bulow et al. 2015; Seaby et al. 2017). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage. Based on the collective evidence, the c.1096-1G>C variant is classified as pathogenic for Noonan syndrome-like disorder with juvenile myelomonocytic leukemia. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Dec 17, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	RASopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002243231.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 25952305‚ 25358541 Comment: show ClinVar contains an entry for this variant (Variation ID: 45196). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 25952305). Disruption of this splice site has been observed in individual(s) with CBL-related conditions (PMID: 25358541; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 of the CBL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 26, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Ambry exome assertion method (8-5-2015))	Inborn genetic diseases	Ambry Genetics Accession: SCV000742135.4 First in ClinVar: Apr 15, 2018 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 20694012 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Clinical Features: Spastic paraparesis (present) , Gait disturbance (present) , Pes planus (present) , Expressive language delay (present) , Microcephaly (present) , Joint hypermobility (present) , Hypermelanotic macule (present) , Broad skull (present) , Low posterior hairline (present) , Cupped ear (present) , Low-set ears (present) , Pectus excavatum (present) , Abnormality of the palate (present) , Abnormal hair whorl (present) Sex: female Ethnicity/Population group: Unknown

Comment:

The 1096-1G>C variant in CBL has been reported in one individual with clinical f eatures of Noonan syndrome and juvenile myelomonocytic leukemia (JMML; Loh 2009, Niemeyer 2010). This variant was reported to be homozygous in a blood sample an d heterozygous in the germline. Studies have shown that the 1096-1G>A variant i mpacts splicing (Niemeyer 2010). In addition, this variant was not identified in either parent of this individual and therefore likely occurred de novo, assumin g that non-medical explanations including alternate paternity or undisclosed ado ption have been ruled out. This finding supports that this variant is disease ca using and responsible for Noonan-like syndrome and juvenile myelomonocytic leuke mia in this individual. In summary, this variant meets our criteria to be classi fied as pathogenic (http://pcpgm.partners.org/LMM).

Comment:

The CBL c.1096-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in a heterozygous state in one child with juvenile myelomonocytic leukemia who also presented with cafÃ©-au-lait spots, juvenile xanthogranuloma, cryptorchidism, poor growth, developmental delay, and supraventricular tachycardia (Niemeyer et al. 2010). In addition, evaluation of non-germline cells in this child and two additional individuals showed the c.1096-1G>C variant present in a either a homozygous or heterozygous state (Loh et al. 2009; Niemeyer et al. 2010; Strullu et al. 2013). The c.1096-1G>C variant is located in intron 7. RT-PCR showed the presence of in-frame protein products lacking exon 8, which encompasses the functionally important RING finger domain (Abbas et al. 2008; Niemeyer et al. 2010). Additional splice site variants at the same genomic position with different base changes have also been described in individuals with RASopathy or Noonan-like phenotypes (Strullu et al. 2013; Bulow et al. 2015; Seaby et al. 2017). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage. Based on the collective evidence, the c.1096-1G>C variant is classified as pathogenic for Noonan syndrome-like disorder with juvenile myelomonocytic leukemia.

Comment:

ClinVar contains an entry for this variant (Variation ID: 45196). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 25952305). Disruption of this splice site has been observed in individual(s) with CBL-related conditions (PMID: 25358541; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 of the CBL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm.	Seaby EG	Frontiers in pediatrics	2017	PMID: 28589114
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
In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia.	Strullu M	Leukemia	2013	PMID: 23823657
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.	Niemeyer CM	Nature genetics	2010	PMID: 20694012
Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.	Loh ML	Blood	2009	PMID: 19571318
Exon 8 splice site mutations in the gene encoding the E3-ligase CBL are associated with core binding factor acute myeloid leukemias.	Abbas S	Haematologica	2008	PMID: 18698078

Submissions - Functional Data

functionally abnormal -- retained intron

assessed by RNAseq

Result:

Intron inclusion between exons 7 & 8

Intron inclusion between exons 7 & 8, based on review of RNA-seq in TCGA-AB-2914-03A tumor which has CBL NM_005188.4:c.1096-1G>C variant

Link: MutSpliceDB

MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Accession: SCV002032106.3

Submitted: 2025-08-14

Assay description:

RNA sequencing

Molecular phenotype measured: mRNA splicing
Collection method: in vivo
Species: human

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion (p=0.0),junction spanning - intron inclusion with mutation (p=0.0),read abundance - intron inclusion (p=0.0)

Modifies a natural acceptor site at NC_000011.9:g.119148875 from 7.98 to -3.69 bits. Significant p-values: junction spanning - intron inclusion (29 reads, p=0.0), junction spanning - intron inclusion with mutation (26 reads, p=0.0), read abundance - intron inclusion (289 reads, p=0.0). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006766707.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-AB-2914), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Acute myeloid leukemia
Transcript: NM_005188.4:c.1096-1G>C
Molecular phenotype measured: splicing
Cell line: TCGA-AB-2914
Tissue: Acute Myeloid Leukemia (LAML)
Collection method: in vitro
Species: human
Number of controls: 233

Text-mined citations for rs397517076 ...

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 Jan 03, 2026

ClinVar Genomic variation as it relates to human health

NM_005188.4(CBL):c.1096-1G>C

Functional data are available for this variant

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Submissions - Functional Data

Text-mined citations for rs397517076 ...