VCV000180824.7 - ClinVar

NM_005188.4(CBL):c.2503C>T (p.Arg835Trp)

Germline

Classification

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

Uncertain significance
Uncertain significance (2)

2 out of 2 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

Variant Details

Identifiers

NM_005188.4(CBL):c.2503C>T (p.Arg835Trp)

Variation ID: 180824 Accession: VCV000180824.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119299563 (GRCh38) [ NCBI UCSC ] 11: 119170273 (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	May 29, 2016	Feb 15, 2026	Oct 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005188.4:c.2503C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005179.2:p.Arg835Trp	missense
NC_000011.10:g.119299563C>T
NC_000011.9:g.119170273C>T
NG_016808.1:g.98284C>T
LRG_608:g.98284C>T

... more HGVS ... less HGVS

Protein change

R835W

Other names

p.R835W:CGG>TGG

Canonical SPDI

NC_000011.10:119299562:C:T

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), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA296011 dbSNP: rs368696716 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	2327	2577

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 provided	Uncertain significance (1)	criteria provided, single submitter	May 22, 2013	RCV000157869.2
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Oct 28, 2024	RCV001850198.6

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.
Uncertain significance (May 22, 2013) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000207799.10 First in ClinVar: Feb 24, 2015 Last updated: May 29, 2016	Comment: show This variant is denoted p.Arg835Trp at the protein level, c.2503C>T at the cDNA level, and results in the change of an Arginine for a Tryptophan (CGG>TGG) in exon 16 of the CBL gene (NM_005188.2). The R835W missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This missense change is a non-conservative amino acid substitution with a positively charged and polar residue (Arg) being replaced by a neutral and non-polar residue (Trp). The residue at which this substitution occurs is highly conserved in the protein. However, no missense mutations have been reported in the CBL gene beyond codon Arginine 420 (Martinelli et al., 2010). The R835W variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, R835W is interpreted as a variant of unknown significance. The variant is found in NOONAN panel(s). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Oct 28, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	RASopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002259705.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Comment: show This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 835 of the CBL protein (p.Arg835Trp). This variant is present in population databases (rs368696716, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 180824). 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 not expected to disrupt CBL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Comment:

This variant is denoted p.Arg835Trp at the protein level, c.2503C>T at the cDNA level, and results in the change of an Arginine for a Tryptophan (CGG>TGG) in exon 16 of the CBL gene (NM_005188.2). The R835W missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This missense change is a non-conservative amino acid substitution with a positively charged and polar residue (Arg) being replaced by a neutral and non-polar residue (Trp). The residue at which this substitution occurs is highly conserved in the protein. However, no missense mutations have been reported in the CBL gene beyond codon Arginine 420 (Martinelli et al., 2010). The R835W variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, R835W is interpreted as a variant of unknown significance. The variant is found in NOONAN panel(s).

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 835 of the CBL protein (p.Arg835Trp). This variant is present in population databases (rs368696716, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 180824). 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 not expected to disrupt CBL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs368696716 ...

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 Feb 15, 2026