Total submissions: 14
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000788006 | SCV000927038 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2019-05-10 | reviewed by expert panel | curation | The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). 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): PS2, PS4, PM2, PP3, PP2. |
| Variantyx, |
RCV000995619 | SCV007593894 | pathogenic | Noonan syndrome 1 | 2025-06-30 | criteria provided, single submitter | clinical testing | This is a nonsynonymous variant in the PTPN11 gene (OMIM: 176876). Pathogenic variants in this gene have been associated with autosomal dominant Noonan syndrome 1. This variant likely occurred de novo in the current proband and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 33619735, 32410215) (PS2). This variant has been reported in several unrelated affected individuals (PMID: 26817465, 32410215, 33619735, 36349709, 29907801) (PS4). It lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the PTPN11 protein (PMID: 26817465) (PM1) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.772) (PP3). This variant has a 0.0063% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar (PP5). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant Noonan syndrome 1. |
| Genetics Laboratory, |
RCV006456636 | SCV007346585 | pathogenic | Pigmentary skin disorders | 2025-12-08 | criteria provided, single submitter | clinical testing | PS4_moderate, PM2_moderate, PP3_supporting, PP2_supporting, PP1_moderate, PS2_strong |
| Ambry Genetics | RCV005462890 | SCV006137568 | likely pathogenic | Cardiovascular phenotype | 2025-05-03 | criteria provided, single submitter | clinical testing | The p.I56V variant (also known as c.166A>G), located in coding exon 3 of the PTPN11 gene, results from an A to G substitution at nucleotide position 166. The isoleucine at codon 56 is replaced by valine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with Noonan syndrome; in at least one individual, it was determined to be de novo (Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Bessis D et al. Br J Dermatol, 2019 Jun;180:1438-1448; Leach NT et al. Genet Med, 2019 Feb;21:417-425; Li R et al. Clin Genet, 2020 Sep;98:215-230; Brunet T et al. Clin Genet, 2021 Jul;100:14-28; Weller K et al. Prenat Diagn, 2024 Oct;44:1288-1295). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| 3billion | RCV000995619 | SCV005905404 | pathogenic | Noonan syndrome 1 | 2024-02-05 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.90 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in the same amino acid change (ClinVar ID: VCV000040485 / PMID: 26817465) and a different missense change at the same codon (p.Ile56Thr / ClinVar ID: VCV000477669) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Genetics and Molecular Pathology, |
RCV000995619 | SCV002761907 | pathogenic | Noonan syndrome 1 | 2021-11-15 | criteria provided, single submitter | clinical testing | The PTPN11 c.166A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid isoleucine at position 56 in the protein to valine. This variant is absent from population databases (PM2), but has been reported at least 4 times in the literature in patients with a clinical presentation of Noonan syndrome or RASopathy (PS4_Moderate). A different pathogenic missense change, p.Ile56Thr, has been reported before at the same amino acid position (PM5). This variant has been identified as a de novo variant in at least two affected patients with no family history of this condition (Li et al, 2020 PMID: 32410215; Brunet et al, 2021 PMID 33619735) (PS2). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40485). The variant has been reported in the HGMD database: CM161482. Computational predictions support a deleterious effect on the gene or gene product (PP3). |
| Genomic Medicine Lab, |
RCV000995619 | SCV001573019 | likely pathogenic | Noonan syndrome 1 | 2020-03-26 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics Munich, |
RCV000995619 | SCV001149898 | likely pathogenic | Noonan syndrome 1 | 2018-06-06 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV000518841 | SCV000927861 | likely pathogenic | not provided | 2018-08-17 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000557839 | SCV000698061 | pathogenic | RASopathy | 2019-11-19 | criteria provided, single submitter | clinical testing | Variant Summary: PTPN11 c.166A>G (p.Ile56Val) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 control chromosomes (gnomAD). The variant, c.166A>G, has been reported in the literature and by clinical laboratories in multiple individuals affected with features of Noonan Syndrome and Related Conditions (Smith_2009, Atik_2016, Leach_2018, ClinVar database). Additionally, one reportedly de novo occurrence was observed by a clinical laboratory (ClinVar database). In addition, this variant was identified at our laboratory in one patient with pulmonary stenosis and ASD. These data indicate that the variant is very likely to be associated with disease. Several mutations in neighboring codons (N58K, N58H, and N58D) have been published in association with Noonan Syndrome, emphasizing the functional importance of this residue and/or SH2 region.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as likely pathogenic (3x) and pathogenic (2x). Based on the evidence outlined above, the variant was re-classified as pathogenic. |
| Labcorp Genetics |
RCV000557839 | SCV000659037 | pathogenic | RASopathy | 2025-05-08 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the PTPN11 protein (p.Ile56Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 26817465; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40485). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000154561 | SCV000204234 | likely pathogenic | Noonan syndrome | 2018-02-27 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Gene |
RCV000518841 | SCV000057358 | pathogenic | not provided | 2023-10-23 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26817465, 29907801, 32410215, 30050098, 29493581, 36555586, 33619735) |
| Prevention |
RCV004528152 | SCV004109387 | pathogenic | PTPN11-related disorder | 2023-12-07 | no assertion criteria provided | clinical testing | The PTPN11 c.166A>G variant is predicted to result in the amino acid substitution p.Ile56Val. This variant has been reported in multiple individuals with Noonan syndrome and in some of these cases was determined to have arisen de novo (Atik et al. 2016. PubMed ID: 26817465; Li et al. 2020. PubMed ID: 32410215; Brunet et al. 2021. PubMed ID: 33619735; Table S3 in Leach et al. 2019. PubMed ID: 29907801). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel on the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/variation/40485). This variant is interpreted as pathogenic. |