VCV000045208.29 - ClinVar

NM_005188.4(CBL):c.2592C>T (p.Leu864=)

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.

(13)

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.

Benign

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.2592C>T (p.Leu864=)

Variation ID: 45208 Accession: VCV000045208.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119299652 (GRCh38) [ NCBI UCSC ] 11: 119170362 (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	Oct 2, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005188.4:c.2592C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005179.2:p.Leu864=	synonymous
NC_000011.10:g.119299652C>T
NC_000011.9:g.119170362C>T
NG_016808.1:g.98373C>T
LRG_608:g.98373C>T
LRG_608t1:c.2592C>T	LRG_608p1:p.Leu864=

... more HGVS ... less HGVS

Protein change

Other names

p.L864L:CTC>CTT

Canonical SPDI

NC_000011.10:119299651:C:T

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.

0.03435 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00787

Exome Aggregation Consortium (ExAC) 0.01002

The Genome Aggregation Database (gnomAD) 0.03391

1000 Genomes Project 0.03435

1000 Genomes Project 30x 0.03482

Trans-Omics for Precision Medicine (TOPMed) 0.03663

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.03688

Links

ClinGen: CA135737 dbSNP: rs1893177 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	1457	1613

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.
not specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Aug 12, 2019	RCV000038363.16
CBL-related disorder	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000404375.5
RASopathy	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000462737.12
Noonan syndrome and Noonan-related syndrome	Benign (1)	criteria provided, single submitter	Jun 18, 2021	RCV001813348.3
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 4, 2018	RCV002453316.2
Juvenile myelomonocytic leukemia	Benign (1)	criteria provided, single submitter	Jul 7, 2023	RCV003315563.1
not provided	Benign (1)	criteria provided, single submitter	-	RCV004707869.1

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310875.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Feb 10, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167558.11 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Mar 19, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062035.5 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Comment: p.Leu864Leu in Exon 16 of CBL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, … (more) p.Leu864Leu in Exon 16 of CBL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 10.6% (398/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1893177). (less) Number of individuals with the variant: 28
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	CBL-related disorder Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000367782.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Aug 12, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362203.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (10) PubMed: 25224413‚ 21828135‚ 23690417‚ 19387008‚ 19901108‚ 20951944‚ 19620960‚ 22733026‚ 29296819‚ 27069254
Benign (Jun 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060500.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile myelomonocytic leukemia Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016967.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Dec 04, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002739385.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005235214.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Feb 01, 2024)	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: SCV000555934.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798172.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807136.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922020.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Leu864Leu in Exon 16 of CBL: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 10.6% (398/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1893177).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy.	Spiegel JY	Blood advances	2017	PMID: 29296819
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.	Arber DA	Blood	2016	PMID: 27069254
TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients.	Bejar R	Blood	2014	PMID: 25224413
Prognostic score including gene mutations in chronic myelomonocytic leukemia.	Itzykson R	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2013	PMID: 23690417
Use of CBL exon 8 and 9 mutations in diagnosis of myeloproliferative neoplasms and myelodysplastic/myeloproliferative disorders: an analysis of 636 cases.	Schnittger S	Haematologica	2012	PMID: 22733026
Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A.	Jankowska AM	Blood	2011	PMID: 21828135
Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling.	Rathinam C	Cancer cell	2010	PMID: 20951944
Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies.	Makishima H	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19901108
Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms.	Sanada M	Nature	2009	PMID: 19620960
Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.	Grand FH	Blood	2009	PMID: 19387008

Text-mined citations for rs1893177 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005188.4(CBL):c.2592C>T (p.Leu864=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1893177 ...