Variant: NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile)

CA261555

40484 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2025-07-08

Published on: 2025-09-25

HGVS expressions

NM_002834.5:c.155C>T
NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile)
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
ENST00000639857.2:c.155C>T
ENST00000685487.1:c.155C>T
ENST00000687906.1:c.155C>T
ENST00000688597.1:c.155C>T
ENST00000690210.1:c.155C>T
ENST00000692624.1:c.155C>T
ENST00000351677.7:c.155C>T
ENST00000639857.1:c.155C>T
ENST00000351677.6:c.155C>T
ENST00000392597.5:c.155C>T
ENST00000635625.1:c.155C>T
NM_002834.3:c.155C>T
NM_080601.1:c.155C>T
NM_001330437.1:c.155C>T
NM_002834.4:c.155C>T
NM_080601.2:c.155C>T
NM_001330437.2:c.155C>T
NM_001374625.1:c.152C>T
NM_080601.3:c.155C>T

Pathogenic

• Met criteria codes: PS2 PS4 PM2_Supporting PP2 PP3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0

Evidence submitted by expert panel

RASopathy VCEP

The c.155C>T (NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile)) variant in PTPN11 is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 52 (p.Thr52Ile). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to PTPN11 function (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 a common mechanism of disease (PP2; PMID: 29493581). This variant has been reported in 11 probands from 9 families with features of Noonan Syndrome (PS4, 8.0 pts.; PMIDs: 22465605, 25804457, 32059087; GeneDx, Partners Laboratory for Molecular Medicine, & Service de Génétique Moléculaire (Hélène Cave) internal data: ClinVar SCV000057357, SCV000061283, & SCV001438499). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with Noonan Syndrome (PS2, 2.0 pts.; Service de Génétique Moléculaire (Hélène Cave) internal data: SCV001438499). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: (PM2_supporting, PP3, PP2, PS4, PS2. (Specification Version 2.3.0, 07/08/25).

Met criteria codes

• PS2: This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual (PS2, 2.0 pts.; Service de Génétique Moléculaire (Helene Cave) internal data: SCV001438499).
• PS4: This variant has been reported in 11 probands from 9 families with features of Noonan Syndrome (PS4, 8.0 pts.; PMIDs: 22465605, 25804457, 32059087; GeneDx, Partners Laboratory for Molecular Medicine, & Service de Génétique Moléculaire (Hélène Cave) internal data: ClinVar SCV000057357, SCV000061283, & SCV001438499).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_supporting). Coverage of the gene in this region is accurate.
• 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. The Z-score for missense variants in PTPN11 in gnomAD v4.1.0 is 4.95 (PP2; PMID: 29493581).
• PP3: The computational predictor REVEL gives a score of 0.912, which is above the threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). In-silico predictors consistently suggest a harmful impact of the mutation (probably damaging by PolyPhen2, Damaging by SIFT, FATHMM, & PROVEAN).