Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000254684 | SCV000057441 | pathogenic | not provided | 2025-01-27 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate this variant results in increased phosphatase activity of the SHP-2 protein (PMID: 24891296); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14982869, 24803665, 27521173, 28746941, 15985475, 19077116, 22465605, 30541462, 31560489, 29493581, 16358218, 15001945, 32737134, 36566191, 33057194, 35904599, 35979676, 35982127, 35982159, 24891296, 17020470) |
Laboratory for Molecular Medicine, |
RCV000157010 | SCV000061277 | pathogenic | Noonan syndrome | 2020-09-02 | criteria provided, single submitter | clinical testing | The p.Pro491Ser variant in PTPN11 has been identified in more than 10 individuals with clinical features of Noonan syndrome, including one individual in whom it occurred de novo (Bertola 2006 PMID: 17020470; Tartaglia 2006 PMID: 16358218; Yang 2018 PMID: 30541462; LMM data). This variant has also been identified as a somatic change occurring in an individual with acute lymphoblastic leukemia (Tartaglia 2004 PMID: 14982869). It has been identified in 0.001% (1/113754) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID 40550). Additionally, several other pathogenic changes (p.Pro491Thr; p.Pro491Leu; p.Pro491His) have been identified at this position, suggesting that this residue is critical to the function of the protein. In vitro functional studies support an impact on protein function (Edwards 2014 PMID: 24891296). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP codes applied: PS4, PM5_Strong, PM6, PS3_Supporting. |
Labcorp Genetics |
RCV000033536 | SCV000549982 | pathogenic | RASopathy | 2023-09-23 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 19621452, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. ClinVar contains an entry for this variant (Variation ID: 40550). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 16358218, 17020470, 19077116, 22465605). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs397507539, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 491 of the PTPN11 protein (p.Pro491Ser). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000033536 | SCV000920099 | pathogenic | RASopathy | 2019-11-18 | criteria provided, single submitter | clinical testing | Variant summary: Variant summary: PTPN11 c.1471C>T (p.Pro491Ser) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain and Tyrosine specific protein phosphatases domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found in 1/246860 control chromosomes, a frequency of 4.1e-06. c.1471C>T has been reported in the literature in numerous individuals affected with Noonan Syndrome or related disorders, indicating the variant is very likely to be associated with disease. In addition, several variants causing a change at the same codon have been reported as associated with Noonan Syndrome (p.P491A, p.P491H, p.P491L, p.P491T), suggesting the proline is critical for proper gene function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Genetic Testing Center for Deafness, |
RCV000984919 | SCV000992411 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | case-control | ||
ARUP Laboratories, |
RCV000157010 | SCV001156694 | pathogenic | Noonan syndrome | 2019-06-26 | criteria provided, single submitter | clinical testing | The PTPN11 c.1471C>T; p.Pro491Ser variant (rs397507539) is reported in the literature in multiple individuals affected with Noonan syndrome (Aoki 2008, Rasmussen 2008, Tartaglia 2006, van Trier 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40550). The proline at codon 491 is highly conserved, and functional assays suggest this variant causes increased phosphatase activity of the PTPN11 protein (Edwards 2014). Additionally, other amino acid substitutions at this codon (p.Pro491His, p.Pro491Leu, p.Pro491Phe) have been reported in individuals with Noonan syndrome and are considered disease-causing (Aoki 2008, Binder 2005, Schuettpelz 2009, Tartaglia 2006). Based on available information, the p.Pro491Ser variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Edwards JJ et al. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. Rasmussen KJ et al. Bile duct anomalies in a male child with Noonan syndrome: a case for ras and notch pathway synergism. Am J Med Genet A. 2008 Jan 15;146A(2):261-3. Schuettpelz LG et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer. 2009 Dec;53(6):1147-9. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. van Trier DC et al. Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients. Ophthalmology. 2016 Oct;123(10):2137-46. |
Ce |
RCV000254684 | SCV001247469 | pathogenic | not provided | 2021-12-01 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001813257 | SCV002060562 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2021-01-14 | criteria provided, single submitter | clinical testing | |
Ai |
RCV000254684 | SCV002501600 | pathogenic | not provided | 2021-12-27 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics | RCV000254684 | SCV002770732 | pathogenic | not provided | 2021-12-16 | criteria provided, single submitter | clinical testing | |
Juno Genomics, |
RCV004795948 | SCV005416204 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | criteria provided, single submitter | clinical testing | PM2_Supporting+PS4+PM6_Strong+PP4+PP2 | |
Baylor Genetics | RCV000033536 | SCV000196652 | pathogenic | RASopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines | |
Biochemical Molecular Genetic Laboratory, |
RCV000984919 | SCV001132827 | pathogenic | Noonan syndrome 1 | 2019-01-29 | no assertion criteria provided | clinical testing |