NM_005188.4(CBL):c.1253T>C (p.Phe418Ser) AND RASopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 3, 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:: RCV003772177.2

Allele description [Variation Report for NM_005188.4(CBL):c.1253T>C (p.Phe418Ser)]

NM_005188.4(CBL):c.1253T>C (p.Phe418Ser)

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.1253T>C (p.Phe418Ser)

HGVS:

NC_000011.10:g.119278535T>C
NG_016808.1:g.77256T>C
NM_005188.4:c.1253T>CMANE SELECT
NP_005179.2:p.Phe418Ser
LRG_608t1:c.1253T>C
LRG_608:g.77256T>C
NC_000011.9:g.119149245T>C
NM_005188.2:c.1253T>C
NM_005188.3:c.1253T>C

Protein change:

F418S

Links:

dbSNP: rs772156285

NCBI 1000 Genomes Browser:

rs772156285

Molecular consequence:

NM_005188.4:c.1253T>C - 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
SCV004686106	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23823657, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004686106

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 3, 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

In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia.

Strullu M, Caye A, Cassinat B, Fenneteau O, Touzot F, Blauwblomme T, Rodriguez R, Latour S, Petit A, Barlogis V, Galambrun C, Leblanc T, Baruchel A, Chomienne C, Cavé H.

Leukemia. 2013 Dec;27(12):2404-7. doi: 10.1038/leu.2013.203. Epub 2013 Jul 4. No abstract available.

PubMed [citation]

PMID:: 23823657

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, SCV004686106.1

#	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 phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 418 of the CBL protein (p.Phe418Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neutrophilic dermatosis (PMID: 23823657). ClinVar contains an entry for this variant (Variation ID: 1327077). 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. 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: Sep 29, 2024

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