NM_002834.5(PTPN11):c.1282G>C (p.Val428Leu) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 17, 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:: RCV001879977.4

Allele description [Variation Report for NM_002834.5(PTPN11):c.1282G>C (p.Val428Leu)]

NM_002834.5(PTPN11):c.1282G>C (p.Val428Leu)

Gene:

PTPN11:protein tyrosine phosphatase non-receptor type 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.13

Genomic location:

Preferred name:

NM_002834.5(PTPN11):c.1282G>C (p.Val428Leu)

HGVS:

NC_000012.12:g.112486532G>C
NG_007459.1:g.72801G>C
NM_001330437.2:c.1294G>C
NM_001374625.1:c.1279G>C
NM_002834.5:c.1282G>CMANE SELECT
NM_080601.3:c.1282G>C
NP_001317366.1:p.Val432Leu
NP_001361554.1:p.Val427Leu
NP_002825.3:p.Val428Leu
NP_542168.1:p.Val428Leu
LRG_614t1:c.1282G>C
LRG_614:g.72801G>C
NC_000012.11:g.112924336G>C
NM_002834.3:c.1282G>C

Protein change:

V427L

Links:

dbSNP: rs397507536

NCBI 1000 Genomes Browser:

rs397507536

Molecular consequence:

NM_001330437.2:c.1294G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.1279G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.1282G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.1282G>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
SCV002207955	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 17, 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

SCV002207955

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 17, 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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002207955.3

#	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 leucine, which is neutral and non-polar, at codon 428 of the PTPN11 protein (p.Val428Leu). For these reasons, this variant has been classified as Pathogenic. A different variant (c.1282G>T) giving rise to the same protein effect has been determined to be pathogenic (PMID: 24451042; Invitae). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 978848). 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 PTPN11 protein function.

#	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: Mar 5, 2024

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