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.155C>T (p.Thr52Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA261555

40484 (ClinVar)

Gene: PTPN11

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c650daaa-d00c-411a-9439-fe0b0570e53e

Approved on: 2020-05-18

Published on: 2020-07-01

HGVS expressions

NM_002834.4:c.155C>T

NM_002834.4(PTPN11):c.155C>T (p.Thr52Ile)

NM_002834.3:c.155C>T

NM_080601.1:c.155C>T

NM_001330437.1:c.155C>T

NM_080601.2:c.155C>T

NM_001330437.2:c.155C>T

NM_001374625.1:c.152C>T

NM_002834.5:c.155C>T

NM_080601.3:c.155C>T

ENST00000351677.6:c.155C>T

ENST00000392597.5:c.155C>T

ENST00000635625.1:n.155C>T

NC_000012.12:g.112450335C>T

CM000674.2:g.112450335C>T

NC_000012.11:g.112888139C>T

CM000674.1:g.112888139C>T

NC_000012.10:g.111372522C>T

NG_007459.1:g.36604C>T

Pathogenic

PS4 PP3 PP2 PM2 PM6

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.155C>T (p.Thr52Ile) variant in PTPN11 has been identified in more than 5 independent occurrences in patients with a RASopathy (PS4; PMID: 22465605, 25804457, 32059087, GeneDx, Partners Laboratory for Molecular Medicine, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; ClinVar SCV000057357.11, SCV000061283.5). It was observed as a de novo occurrence without maternity or paternity confirmed in one proband with clinical features of a RASopathy (PM6; Hopital Universitaire Robert Debre internal data). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr52Ile variant may impact the protein (PP3). The variant is located in the PTPN11 gene, which 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 pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6_Strong, PM2, PP2, PP3.

PS4

The c.155C>T (p.Thr52Ile) variant in PTPN11 has been identified in at least 5 independent occurrences in patients with a RASopathy (PS4; PMID: 22465605, 25804457, 32059087, GeneDx, Partners Laboratory for Molecular Medicine, Institute of Human Genetics, Otto von Guericke University Magdeburg, Hopital Universitaire Robert Debre internal data, ClinVar SCV000057357.11; SCV000061283.5).

PP3

Computational prediction tools and conservation analysis suggest that the p.Thr52Ile variant may impact the protein (PP3).

PP2

The variant is located in the PTPN11 gene, which 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).

PM2

Absent from both versions of gnomAD.

PM6

This variant was observed as a de novo occurrence without confirmed maternity/paternity in one proband with clinical features of a RASopathy (PM6; Hopital Universitaire Robert Debre internal data).

Curation History

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