NM_005188.4(CBL):c.1259G>A (p.Arg420Gln) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000816470.15

Allele description [Variation Report for NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)]

NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)

Gene:

CBL:Cbl proto-oncogene [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)

HGVS:

NC_000011.10:g.119278541G>A
NG_016808.1:g.77262G>A
NM_005188.4:c.1259G>AMANE SELECT
NP_005179.2:p.Arg420Gln
NP_005179.2:p.Arg420Gln
LRG_608t1:c.1259G>A
LRG_608:g.77262G>A
LRG_608p1:p.Arg420Gln
NC_000011.9:g.119149251G>A
NM_005188.2:c.1259G>A
NM_005188.3:c.1259G>A
NM_005188.4:c.1259G>A
P22681:p.Arg420Gln

Protein change:

R420Q; ARG420GLN

Links:

UniProtKB: P22681#VAR_064335; OMIM: 165360.0004; dbSNP: rs267606708

NCBI 1000 Genomes Browser:

rs267606708

Molecular consequence:

NM_005188.4:c.1259G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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carcinoembryonic antigen-related cell adhesion molecule 19 isoform 2 precursor [...
carcinoembryonic antigen-related cell adhesion molecule 19 isoform 2 precursor [Homo sapiens]
gi|45267817|ref|NP_064604.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000956980	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 12, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 33318624, 17446348, 20619386, 22246246, 25178484, 33627783, 28492532
SCV003922954	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 7, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 22190897, 25224413, 21828135, 23690417, 19387008, 19901108, 20951944, 19620960, 22733026, 29296819, 17446348, 25178484, 20619386, 23010802, 27069254, 33318624 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000956980

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 12, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV003922954

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 7, 2023)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Makishima H, Sugimoto Y, Szpurka H, Clemente MJ, Ng KP, Muramatsu H, O'Keefe C, Saunthararajah Y, Maciejewski JP.

Leukemia. 2012 Jul;26(7):1547-54. doi: 10.1038/leu.2012.7. Epub 2012 Jan 13.

PubMed [citation]

PMID:: 22246246

E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis.

Ahmed SF, Buetow L, Gabrielsen M, Lilla S, Sibbet GJ, Sumpton D, Zanivan S, Hedley A, Clark W, Huang DT.

Oncogene. 2021 Mar;40(12):2149-2164. doi: 10.1038/s41388-021-01684-x. Epub 2021 Feb 24.

PubMed [citation]

PMID:: 33627783
PMCID:: PMC7994203

See all PubMed Citations (19)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000956980.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the CBL protein (p.Arg420Gln). This variant is present in population databases (rs267606708, gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 20619386, 33318624). ClinVar contains an entry for this variant (Variation ID: 13810). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CBL protein function. Experimental studies have shown that this missense change affects CBL function (PMID: 17446348, 20619386, 22246246, 25178484, 33627783). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922954.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: CBL c.1259G>A (p.Arg420Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the RING-type Zinc finger (IPR001841) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251418 control chromosomes. c.1259G>A has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (e.g. Digilio_2010, Kauffmann_2021, Martinelli_2010). These data indicate that the variant is likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function, finding that the variant inhibits CBL ubiquitin ligase function and EGFR trafficking (Sargin_2007, Martinelli_2010, Brand_2014). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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