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.1403C>T (p.Thr468Met)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA220134

13331 (ClinVar)

Gene: PTPN11

Condition: Noonan syndrome with multiple lentigines

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e33078e1-353c-43ad-a6d9-93f2dab20e33

Approved on: 2017-04-03

Published on: 2019-07-15

HGVS expressions

NM_002834.4:c.1403C>T

NM_002834.4(PTPN11):c.1403C>T (p.Thr468Met)

NC_000012.12:g.112488466C>T

CM000674.2:g.112488466C>T

NC_000012.11:g.112926270C>T

CM000674.1:g.112926270C>T

NC_000012.10:g.111410653C>T

NG_007459.1:g.74735C>T

NM_002834.3:c.1403C>T

NM_001330437.1:c.1415C>T

ENST00000351677.6:c.1403C>T

ENST00000635625.1:n.1415C>T

ENST00000635652.1:n.416C>T

Pathogenic

PM6_Strong PS4 PS3 PP3 PP2 PM1 PP1_Strong

PM2

Evidence Links 12

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (PM1; PMID 29493581). 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). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). 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): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3.

PM6_Strong

The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 25884655, 19864201 ).

3 cases with p.Thr468Met and 2 of them are assumed de novo PubMed:19864201

Patient with NSML and de novo p.Thr468Met variant PubMed:25884655

PS4

Added this code since the Gelb 2018 paper. There are more than 5 independent occurrences of the variant in NSML patients. PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399

1 proband PubMed:24767283

1 proband PubMed:17935252

identified in 5 unrelated probands and one mother daughter pair PubMed:12058348

1 proband PubMed:20883402

1 proband PubMed:15520399

PS3

In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586).

Mutant exhibited reduced catalytic activity PubMed:24935154

Variant was found to have gain-of-function effects during Drosophila development PubMed:18849586

Variant exhibited enhanced phosphopeptide binding affinity PubMed:18372317

p.Thr468Met mutant altered activity PubMed:16638574

PP3

Computational prediction tools and conservation analysis suggest that the p.Thr468Met 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).

PM1

The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (PM1; PMID 29493581).

ClinGen RAS EP decided this AA is located in a hotspot PubMed:29493581

PP1_Strong

The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402).

1 segregation (Father and son affected with the variant.) PubMed:24767283

1 segregation from father to son with NSML syndrome PubMed:17935252

3 segregations (1 from 3 different families) PubMed:15520399

2 segregations in patients with NSML PubMed:20883402

PM2

This variant is present in 1/6614 European Finnish alleles. Despite initial application of this code in the Gelb 2018 paper, this criteria should not be applied.

Curation History

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