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.392A>G (p.Lys131Arg)

CA134665

44607 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8586051d-c6a7-40c5-bec9-54228dc29a69

HGVS expressions

NM_002834.4:c.392A>G

NM_002834.4(PTPN11):c.392A>G (p.Lys131Arg)

NC_000012.12:g.112453254A>G

CM000674.2:g.112453254A>G

NC_000012.11:g.112891058A>G

CM000674.1:g.112891058A>G

NC_000012.10:g.111375441A>G

NG_007459.1:g.39523A>G

NM_002834.3:c.392A>G

NM_080601.1:c.392A>G

NM_001330437.1:c.392A>G

NM_080601.2:c.392A>G

ENST00000351677.6:c.392A>G

ENST00000392597.5:c.392A>G

ENST00000635625.1:n.392A>G

Likely Benign

BS1 BP5

BS2 PP2

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). 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 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Université Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5.

BS1

Present in 14/19952 (.04242% with 95% CI) of East Asian alleles in gnomAD

BP5

Patient with Noonan Syndrome with pathogenic variant c.389A>G (p.Y130C) in MAP2K2 as well as the PTPN11 variant (Laboratory for Molecular Medicine internal data). GeneDx also identified a patient with both variants, but lacked phenotypic data.

BS2

Variant observed in a proband inherited from asymptomatic father. 3 well phenotyped individuals required to apply BS2.

Variant identified in study of 158 genes causally implicated in carcinogenesis using WGS from an ancestrally diverse cohort of 681 healthy individuals. No phenotypic data available. PubMed:24728327

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). Although this variant meets PP2 there is case level data supporting a benign classification and therefore it is not applied.

Approved on: 2019-08-19

Published on: 2019-12-03

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