11-119278181-T-G

Variant names:

• chr11-119278181-T-G
• rs267606706
• NM_005188.4:c.1111T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005188.4(CBL):​c.1111T>G​(p.Tyr371Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y371S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CBL NM_005188.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67
• Publications: 2 publications found

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]

CBL Gene-Disease associations (from GenCC):

• CBL-related disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
• juvenile myelomonocytic leukemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain 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 chr11-119278182-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 548022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 11-119278181-T-G is Pathogenic according to our data. Variant chr11-119278181-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2137268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005188.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.1111T>G	p.Tyr371Asp	missense	Exon 8 of 16	NP_005179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	ENST00000264033.6	TSL:1 MANE Select	c.1111T>G	p.Tyr371Asp	missense	Exon 8 of 16	ENSP00000264033.3
	CBL	ENST00000634586.1	TSL:5	c.1111T>G	p.Tyr371Asp	missense	Exon 8 of 18	ENSP00000489218.1
	CBL	ENST00000637974.1	TSL:5	c.1105T>G	p.Tyr369Asp	missense	Exon 8 of 17	ENSP00000490763.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450022 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722298

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101236

Other (OTH) AF: 0.00 AC: 0 AN: 59950

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CBL-related disorder Pathogenic:1

Jul 30, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 20694012, 27609087). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6); 3Cnet: 0.99 (>=0.6)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV002137268). Different missense changes at the same codon (p.Tyr371Asn, p.Tyr371Cys, p.Tyr371His, p.Tyr371Phe, p.Tyr371Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013811, VCV000029824, VCV000180827, VCV000548022, VCV000949693 / PMID: 19571318, 28343148 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:1

May 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in an individual with juvenile myelomonocytic leukemia (JMML) and Noonan-like syndrome in the published literature (Niemeyer et al., 2010); Published functional studies demonstrate that p.(Y371D) results in abnormal protein function (Buetow et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25939664, 20619386, 22315494, 20694012, 27609087)

RASopathy Pathogenic:1

Aug 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 371 of the CBL protein (p.Tyr371Asp). This variant is not present in population databases (gnomAD no frequency). Experimental studies have shown that this missense change affects CBL function (PMID: 27609087). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBL protein function. This variant has not been reported in the literature in individuals affected with CBL-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr371 amino acid residue in CBL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20694012, 23696637, 25283271, 25952305). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.77		Gain of disorder (P = 0.0154)
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.97
gMVP		0.85
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs267606706; hg19: chr11-119148891; COSMIC: COSV50630036;