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_002834.5(PTPN11):c.209A>G (p.Lys70Arg)

CA261568

44603 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3b04afbf-2784-4140-8597-2108c5253464

HGVS expressions

NM_002834.5:c.209A>G

NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg)

NM_002834.3:c.209A>G

NM_080601.1:c.209A>G

NM_001330437.1:c.209A>G

NM_002834.4:c.209A>G

NM_080601.2:c.209A>G

NM_001330437.2:c.209A>G

NM_001374625.1:c.206A>G

NM_080601.3:c.209A>G

ENST00000351677.6:c.209A>G

ENST00000392597.5:c.209A>G

ENST00000635625.1:n.209A>G

NC_000012.12:g.112450389A>G

CM000674.2:g.112450389A>G

NC_000012.11:g.112888193A>G

CM000674.1:g.112888193A>G

NC_000012.10:g.111372576A>G

NG_007459.1:g.36658A>G

Pathogenic

PS4 PP2 PP1 PM2 PM6 PM1

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID: 29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID: 29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). 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). Finally, PTPN11 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, PM1, PM2, PP1, PP2.

PS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

Absent from gnomAD

PM6

PubMed:29084544

PM1

Defined hotspot between N-SH2 and PTPN domains

Approved on: 2020-06-25

Published on: 2020-06-25

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