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

CA261555

40484 (ClinVar)

Gene: PTPN11

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

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

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

• Met criteria codes: PP3 PP2 PM2 PM6 PS4

Expert Panel

RASopathy VCEP

Criteria Specification Information

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.

Met criteria codes

• 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).
• 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).

Approved on: 2020-05-18

Published on: 2020-07-01