ClinVar Genomic variation as it relates to human health

The p.Asp106Ala variant in PTPN11 has been reported in >10 individuals with Noonan syndrome-related disorders and non-immune hydrops fetalis. It segregated with disease in 2 affected individuals from 1 family (Tartaglia 2002, Bertola 2006, Tartaglia 2006, Hung 2007, Shaw 2007, Pierpont 2009, Stevenson 2010, Leach 2019, Sparks 2019). It has additionally been observed at the Laboratory for Molecular Medicine in 7 individuals, 5 with Noonan syndrome-like features and 1 with pulmonary stenosis. The variant was found to be de novo in 1 case (LMM Data). This variant was also observed de novo in a patient with Noonan syndrome tested by GeneDx (Clinvar Variation ID: 40506, Accession: SCV000057388.14). It was absent from large population studies. In vitro functional studies provide some evidence that the p.Asp106Ala variant may impact protein function (Keilhack 2005, Chan 2008, Lee 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome-related disorders. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2, PP3, PS3_Supporting.

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18286234). 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: 40506). This missense change has been observed in individuals with Noonan syndrome (PMID: 12717436, 18470943). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 106 of the PTPN11 protein (p.Asp106Ala).

Common missense variant in PTPN11, observed in 2-5% of patients with Noonan syndrome with or without multiple giant-cell lesions (PMID: 18470943, 12717436, 17020470, 16358218, 17339163, 16990350, 19077116, 21204800, 33318624, 11992261); Not observed at significant frequency in large population cohorts (gnomAD); Located in the linker region between the NSH2 and C-SH2 domains of the SHP-2 protein encoded by PTPN11 (PMID: 15987685); 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21204800, 22848035, 28607217, 22420426, 19737548, 16208280, 23584145, 18854871, 31292302, 34930662, 24803665, 19835954, 19077116, 16990350, 17339163, 16358218, 12960218, 23624134, 24451042, 21590266, 25862627, 12717436, 16053901, 17020470, 22488759, 26124496, 30050098, 30410095, 29907801, 32164556, 18286234, 33318624, 29493581, 18470943, 11992261, 36588761, 15987685, 16987887)

ACMG codes:PS3; PS4; PM1; PM2; PP2; PP3

The PTPN11 c.317A>C; p.Asp106Ala variant (rs397507517) is reported in the literature in multiple individuals affected with Noonan syndrome (Bertelloni 2013, Hung 2007, Leach 2019, Pierpont 2009, Shaw 2007, Stevenson 2011, Tartaglia 2002). This variant is also reported in ClinVar (Variation ID: 40506), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 106 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show hyperactivation upon peptide addition (Keilhack 2005). Additionally, another variant at this codon (c.317A>G; p.Asp106Gly) has been reported in individuals with Noonan syndrome (Bertelloni 2013). Based on available information, the p.Asp106Ala variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. Hung CS et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Leach NT et al. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019 Feb;21(2):417-425. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. Shaw AC et al. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32. Stevenson DA et al. Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet. 2011 Dec;80(6):566-73. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63.

The inherited heterozygous missense variant c.317A>C (p.Asp106Ala) identified in exon 3 (of 16) of the PTPN11 gene is a known pathogenic variant that has been reported in multiple unrelated individuals affected with Noonan spectrum disorders (PMID: 32164556, 17339163, 29907801, 19077116,16990350, 21204800, 11992261). This variant is reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID:40506). This variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. In vitro functional analyses suggest that this variant (located in the linker region between the NSH2 and C-SH2 domains of the PTPN11 protein) results in an increased activity due to misfolding of the inter-SH2 domain linker (PMID:15987685, 18286234). Based on the available evidence, the inherited heterozygous c.317A>C (p.Asp106Ala) variant identified in the PTPN11 gene is reported as Pathogenic.

Variant classified using ACMG guidelines