NM_005188.4(CBL):c.2350G>A (p.Val784Met) AND RASopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000467413.8

Allele description [Variation Report for NM_005188.4(CBL):c.2350G>A (p.Val784Met)]

NM_005188.4(CBL):c.2350G>A (p.Val784Met)

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.2350G>A (p.Val784Met)

HGVS:

NC_000011.10:g.119298456G>A
NG_016808.1:g.97177G>A
NM_005188.4:c.2350G>AMANE SELECT
NP_005179.2:p.Val784Met
NP_005179.2:p.Val784Met
LRG_608t1:c.2350G>A
LRG_608:g.97177G>A
LRG_608p1:p.Val784Met
NC_000011.9:g.119169166G>A
NM_005188.2:c.2350G>A
NM_005188.3:c.2350G>A

Protein change:

V784M

Links:

dbSNP: rs140725852

NCBI 1000 Genomes Browser:

rs140725852

Molecular consequence:

NM_005188.4:c.2350G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543497	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24451042, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543497

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 28, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Diagnosis of Noonan syndrome and related disorders using target next generation sequencing.

Lepri FR, Scavelli R, Digilio MC, Gnazzo M, Grotta S, Dentici ML, Pisaneschi E, Sirleto P, Capolino R, Baban A, Russo S, Franchin T, Angioni A, Dallapiccola B.

BMC Med Genet. 2014 Jan 23;15:14. doi: 10.1186/1471-2350-15-14.

PubMed [citation]

PMID:: 24451042
PMCID:: PMC3915031

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543497.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 784 of the CBL protein (p.Val784Met). This variant is present in population databases (rs140725852, gnomAD 0.006%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 24451042). ClinVar contains an entry for this variant (Variation ID: 40422). 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 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.

#	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: Nov 24, 2024

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