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]

Link to SEPIO compliant JSON-LD document

Variant: NM_002834.4(PTPN11):c.782T>G (p.Leu261Arg)

CA10603294

280939 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a029ca40-8429-42ac-a998-a260aca9fc91

HGVS expressions

NM_002834.4:c.782T>G

NM_002834.4(PTPN11):c.782T>G (p.Leu261Arg)

NM_002834.3:c.782T>G

NM_080601.1:c.782T>G

NM_001330437.1:c.782T>G

NM_080601.2:c.782T>G

NM_001330437.2:c.782T>G

NM_001374625.1:c.779T>G

NM_002834.5:c.782T>G

NM_080601.3:c.782T>G

ENST00000351677.6:c.782T>G

ENST00000392597.5:c.782T>G

ENST00000635625.1:n.782T>G

NC_000012.12:g.112472969T>G

CM000674.2:g.112472969T>G

NC_000012.11:g.112910773T>G

CM000674.1:g.112910773T>G

NC_000012.10:g.111395156T>G

NG_007459.1:g.59238T>G

Uncertain Significance

PP2 PM1 PM2

PS4 PP3 PM5

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.782T>G (p.Leu261Arg) variant in PTPN11 was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in several individuals whose features appear suggestive of a RASopathy; however, none were sufficiently phenotyped or received clinical diagnoses of a RASopathy (PS4 not met). This variant occurs in a region defined by the ClinGen RASopathy Expert Panel as a mutational hotspot of PTPN11 (PM1; PMID: 29493581). Additionally, the Expert Panel has defined PTPN11 as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the clinical significance of this variant is uncertain based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM1, PM2, 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.

PM2

Absent from gnomAD.

PS4

This variant was observed in several individuals whose features appeared suggestive of a RASopathy, however none were sufficiently phenotyped or received clinical diagnoses of a RASopathy (PS4 not met).

PP3

REVEL score 0.555.

PM5

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

Approved on: 2020-03-16

Published on: 2020-03-24

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