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]

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Variant: NM_002834.4(PTPN11):c.781C>T (p.Leu261Phe)

CA235373

40520 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 90bd1343-a396-445b-985c-d23c393118d4

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_002834.4:c.781C>T

NM_002834.4(PTPN11):c.781C>T (p.Leu261Phe)

NM_002834.3:c.781C>T

NM_080601.1:c.781C>T

NM_001330437.1:c.781C>T

NM_080601.2:c.781C>T

ENST00000351677.6:c.781C>T

ENST00000392597.5:c.781C>T

ENST00000635625.1:n.781C>T

NC_000012.12:g.112472968C>T

CM000674.2:g.112472968C>T

NC_000012.11:g.112910772C>T

CM000674.1:g.112910772C>T

NC_000012.10:g.111395155C>T

NG_007459.1:g.59237C>T

Pathogenic

PP2 PM2 PM1 PS4_Moderate PM6_Strong

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.781C>T (p.Leu261Phe) 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 22465605; GeneDx, Cave lab internal data ClinVar SCV000057404.12). The p.Leu261Phe variant has also been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; SCV000061319.5, SCV000207687.1 PMID: 22465605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (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). 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_Moderate, PM2, PM1, PP2.

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

This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).

PM1

Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).

Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). PubMed:29493581

PS4_Moderate

The p.Leu261Phe variant has also been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; SCV000061319.5, SCV000207687.1 PMID: 22465605).

PM6_Strong

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