rs267606704

Positions:

• chr11-119278170-A-C
• chr11-119278170-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_005188.4(CBL):​c.1100A>C​(p.Gln367Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q367K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 8.95

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a region_of_interest Linker (size 28) in uniprot entity CBL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005188.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119278169-C-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 11-119278170-A-C is Pathogenic according to our data. Variant chr11-119278170-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119278170-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBL	NM_005188.4	c.1100A>C	p.Gln367Pro	missense_variant	8/16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6	c.1100A>C	p.Gln367Pro	missense_variant	8/16	1	NM_005188.4	ENSP00000264033	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

CBL-related disorder Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Dec 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 10, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 13, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PM1, PM2, PM5, PP2, PP3, PP5 -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2017

- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 30, 2017

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. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2021

For these reasons, this variant has been classified as Pathogenic. 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"). 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). This variant is not present in population databases (ExAC no frequency). 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. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;.;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.60		Loss of ubiquitination at K362 (P = 0.1044);Loss of ubiquitination at K362 (P = 0.1044);Loss of ubiquitination at K362 (P = 0.1044);.;
MVP		0.98
MPC		0.85
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606704; hg19: chr11-119148880; COSMIC: COSV50632131;