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.205G>C (p.Glu69Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA261565

40498 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9d27348b-e93e-42e4-ad51-7528c854b07d

Approved on: 2019-12-05

Published on: 2019-12-05

HGVS expressions

NM_002834.4:c.205G>C

NM_002834.4(PTPN11):c.205G>C (p.Glu69Gln)

NC_000012.12:g.112450385G>C

CM000674.2:g.112450385G>C

NC_000012.11:g.112888189G>C

CM000674.1:g.112888189G>C

NC_000012.10:g.111372572G>C

NG_007459.1:g.36654G>C

NM_002834.3:c.205G>C

NM_080601.1:c.205G>C

NM_001330437.1:c.205G>C

NM_080601.2:c.205G>C

ENST00000351677.6:c.205G>C

ENST00000392597.5:c.205G>C

ENST00000635625.1:n.205G>C

Pathogenic

PS2_Very Strong PS4 PP2 PP3 PM1 PM2

PP1 PM5

Evidence Links 7

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID: 12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hématologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hématologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID: 26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID: 29493581). 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). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3.

PS2_Very Strong

Institut Universitaire d'Hématologie saw 5 de novo probands with typical or moderate NS (unpublished data). [Applied as PS2_VS because no option for PM6_VS]

PS4

8 probands published in the literature. 2 other probands from Atik et al. 2016 (PMID: 26817465), but only the protein change, not the cDNA change, was specified. 1 additional de novo prenatal case from Croonen et al. 2013 (PMID: 23321623), but no postnatal phenotype data was available. Invitae saw 3 probands with this variant who had diagnoses of NS, as well as 2 probands without a formal diagnosis (SCV000659043.3). Institut Universitaire d'Hématologie saw this variant in 14 probands with NS, including 5 de novo and 1 proband who inherited the variant from an affected parent (unpublished data). EGL, Fulgent, GeneDx, and LMM also saw probands with this variant, but none had a formal diagnosis of a RASopathy.

PubMed:23624134

PubMed:20186801

PubMed:31560489

PubMed:26607044

PubMed:12634870

PubMed:25862627

PubMed:15001945

PP2

This is a missense variant in PTPN11, a missense-constrained gene.

PP3

REVEL score 0.726. No mammals in the UCSC database had an alternate amino acid at this site. Alamut does not predict an impact to splicing.

PM1

Occurs in part of the N-SH2 domain.

PM2

Absent from gnomAD with high coverage.

PP1

Institut Universitaire d'Hématologie saw 1 proband who inherited the variant from an affected parent (unpublished data).

PM5

2 other variants in this codon, but both are likely path, not path, in ClinVar (ClinVar ID: 164997, 224414).

Curation History

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