Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_002834.4(PTPN11):c.782T>A (p.Leu261His)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA6798648

575203 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: eca12c54-c803-4707-851b-c939f2efad43

Approved on: 2020-03-16

Published on: 2020-03-24

HGVS expressions

NM_002834.4:c.782T>A

NM_002834.4(PTPN11):c.782T>A (p.Leu261His)

NC_000012.12:g.112472969T>A

CM000674.2:g.112472969T>A

NC_000012.11:g.112910773T>A

CM000674.1:g.112910773T>A

NC_000012.10:g.111395156T>A

NG_007459.1:g.59238T>A

NM_002834.3:c.782T>A

NM_080601.1:c.782T>A

NM_001330437.1:c.782T>A

NM_080601.2:c.782T>A

NM_001330437.2:c.782T>A

NM_001374625.1:c.779T>A

NM_002834.5:c.782T>A

NM_080601.3:c.782T>A

ENST00000351677.6:c.782T>A

ENST00000392597.5:c.782T>A

ENST00000635625.1:n.782T>A

Likely Pathogenic

PP2 PM1 PS4

PP3 PM5 PM2 PS3

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.782T>A (p.Leu261His) variant in PTPN11 is present in 1/6064 “other” alleles in gnomAD v2.1.1; however, it is absent from gnomAD v3 (PM2 not met). It has been identified in 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 28074573, 22253195, 23756559). A functional assay performed on this variant does not meet approved RASopathy VCEP guidelines for criteria application (PS3 not met; PMID: 28074573). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of PTPN11 (PM1; PMID 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM1, PP2.

PP2

PTPN11 is a missense-constrained gene.

PM1

Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284.

PS4

This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559).

PubMed:22253195

PubMed:28074573

PubMed:23756559

PP3

REVEL score 0.558.

PM5

While pathogenic variants have been reported at this site (ClinVar ID: 40520), PM5 was not applied as PM1 is already met.

PM2

Absent from gnomAD v3, but present in 1/6064 “Other” chromosomes in gnomAD v2.1.1

PS3

The SHP2L261H mutant was documented to enhance ERK phosphorylation when HEK293 cells were treated with higher doses of growth factor and behaved as the most activating mutant following stimulation with 100 ng/ml of EGF, suggesting either a quantitatively milder or qualitatively distinct activating effect on MAPK signaling. PS3 not applicable (SHP2 phosphatase activity approved assay: increased dephosphorylation)

SHP2L261H mutant was documented to enhance ERK phosphorylation when HEK293 cells were treated with higher doses of growth factor and behaved as the most activating mutant following stimulation with 100 ng/ml EGF, suggesting either a quantitatively milder or qualitatively distinct activating effect on MAPK signaling. PS3 not applicable (SHP2 phosphatase activity approved assay: increased dephosphorylation) PubMed:28074573

Curation History

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