VCV000013807.56 - ClinVar

NM_005188.4(CBL):c.1100A>C (p.Gln367Pro)

Germline

Classification

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

Pathogenic/Likely pathogenic

11 out of 13 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.1100A>C (p.Gln367Pro)

Variation ID: 13807 Accession: VCV000013807.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 119278170 (GRCh38) [ NCBI UCSC ] 11: 119148880 (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	Feb 24, 2015	Apr 13, 2025	Oct 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005188.4:c.1100A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005179.2:p.Gln367Pro	missense
NC_000011.10:g.119278170A>C
NC_000011.9:g.119148880A>C
NG_016808.1:g.76891A>C
LRG_608:g.76891A>C
LRG_608t1:c.1100A>C	LRG_608p1:p.Gln367Pro
	P22681:p.Gln367Pro

... more HGVS ... less HGVS

Protein change

Q367P

Other names

p.Q367P:CAA>CCA

Canonical SPDI

NC_000011.10:119278169:A: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.

Links

ClinGen: CA123484 UniProtKB: P22681#VAR_064332 OMIM: 165360.0001 dbSNP: rs267606704 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	1699	1878

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	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 18, 2023	RCV000033352.34
RASopathy	Pathogenic (1)	criteria provided, single submitter	Apr 20, 2021	RCV000702464.13
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Dec 12, 2017	RCV001266923.4
CBL-related disorder	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 10, 2021	RCV001353389.8
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 14, 2018	RCV001813204.4
Noonan syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2017	RCV004017245.1

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 18, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000057257.13 First in ClinVar: Apr 04, 2013 Last updated: Nov 25, 2023	Comment: Published functional studies demonstrate a damaging effect on ubiquitination of target proteins (Sanada et al., 2009); In silico analysis supports that this missense variant has … (more) Published functional studies demonstrate a damaging effect on ubiquitination of target proteins (Sanada et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24458550, 25358541, 20619386, 24803665, 30803559, 19620960, 26449661, 22315494, 35599849) (less)
Pathogenic (Apr 11, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281057.1 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015
Pathogenic (Apr 20, 2021) C Contributing to aggregate classification	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: SCV000831320.8 First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 28492532‚ 20619386‚ 25358541 Comment: This sequence change replaces glutamine with proline at codon 367 of the CBL protein (p.Gln367Pro). The glutamine residue is highly conserved and there is a … (more) This sequence change replaces glutamine with proline at codon 367 of the CBL protein (p.Gln367Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with¬†Noonan¬†or Noonan-like syndrome¬†(PMID: 20619386, 25358541,¬†24458550). ClinVar contains an entry for this variant (Variation ID: 13807). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 10, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	CBL-related disorder (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150037.2 First in ClinVar: Feb 03, 2020 Last updated: Apr 13, 2025	Zygosity: Single Heterozygote Sex: female Tissue: blood
Pathogenic (Mar 01, 2019) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248727.28 First in ClinVar: May 12, 2020 Last updated: Mar 22, 2025	Number of individuals with the variant: 1
Likely pathogenic (Dec 12, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001445104.3 First in ClinVar: Nov 21, 2020 Last updated: Apr 13, 2025	Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Egyptian (Coptic)
Pathogenic (Aug 10, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CBL-related disorder Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976785.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Comment: PM1, PM2, PM5, PP2, PP3, PP5
Pathogenic (Jul 21, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016934.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 14, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060772.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022
Pathogenic (Jun 30, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847496.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (3) PubMed: 20619386‚ 24458550‚ 25358541 Comment: The p.Gln367Pro variant in CBL has been reported as de novo in 4 individuals with clinical features of Noonan syndrome (Martinelli 2010, Hanson 2014, Bulow … (more) The p.Gln367Pro variant in CBL has been reported as de novo in 4 individuals with clinical features of Noonan syndrome (Martinelli 2010, Hanson 2014, Bulow 2015). Additionally, another variant at this position (p.Gln367Lys) has been seen in one family in our lab with clinical features of Noonan syndrome and segregated with disease in 3 affected relatives. This variant has been identified in 1/61496 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs267606704) and in ClinVar (Variation ID# 13807). Computational prediction tools and conservation analysis suggest that the p.Gln367Pro variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for RASopathy disorders in an autosomal dominant manner based upon de novo occurrences. (less)
Pathogenic (May 27, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197390.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 13, 2010) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	NOONAN SYNDROME-LIKE DISORDER WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035073.2 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2017	Publications: PubMed (1) PubMed: 20619386 Comment on evidence: In a boy with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous de novo 1100A-C transversion in the CBL gene, resulting … (more) In a boy with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous de novo 1100A-C transversion in the CBL gene, resulting in a gln367-to-pro (Q367P) substitution in a region adjacent to the linker connecting the RING finger domain to the N-terminal TKB domain. The Q367P mutation was not detected in 400 population-matched controls. Clinical features included dysmorphic facial features, developmental delay, congenital heart defect, and cafe-au-lait spots. In vitro functional expression studies showed that the mutation caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS. (less)
Pathogenic (Dec 22, 2015) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	CBL-related disorder Affected status: yes Allele origin: de novo	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV000599250.1 First in ClinVar: May 01, 2017 Last updated: May 01, 2017
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Comment:

Published functional studies demonstrate a damaging effect on ubiquitination of target proteins (Sanada et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24458550, 25358541, 20619386, 24803665, 30803559, 19620960, 26449661, 22315494, 35599849)

Comment:

This sequence change replaces glutamine with proline at codon 367 of the CBL protein (p.Gln367Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with¬†Noonan¬†or Noonan-like syndrome¬†(PMID: 20619386, 25358541,¬†24458550). ClinVar contains an entry for this variant (Variation ID: 13807). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Gln367Pro variant in CBL has been reported as de novo in 4 individuals with clinical features of Noonan syndrome (Martinelli 2010, Hanson 2014, Bulow 2015). Additionally, another variant at this position (p.Gln367Lys) has been seen in one family in our lab with clinical features of Noonan syndrome and segregated with disease in 3 affected relatives. This variant has been identified in 1/61496 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs267606704) and in ClinVar (Variation ID# 13807). Computational prediction tools and conservation analysis suggest that the p.Gln367Pro variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for RASopathy disorders in an autosomal dominant manner based upon de novo occurrences.

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
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 CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23.	Hanson HL	American journal of medical genetics. Part A	2014	PMID: 24458550
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

Text-mined citations for rs267606704 ...

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 Apr 13, 2025

ClinVar Genomic variation as it relates to human health

NM_005188.4(CBL):c.1100A>C (p.Gln367Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267606704 ...