ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate that the presence of the E76D variant causes increased basal catalytic activity in comparison to wild-type protein (Bocchinfuso et al., 2007); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15987685, 20308328, 24803665, 26607044, 11704759, 28084675, 30417923, 31219622, 31560489, 33318624, 34643321, 17177198, 24077912, 11992261, 9491886, 16053901, 29493581)

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16358218, 16830086, 18678287, 19077116, 22190897). ClinVar contains an entry for this variant (Variation ID: 40503). 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. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 11704759, 15834506, 17177198). For these reasons, this variant has been classified as Pathogenic.

The PTPN11 c.228G>C; p.Glu76Asp variant (rs397507514) is reported in the literature in individuals with Noonan syndrome (Chinton 2019, Li 2019, Tartaglia 2001), and is reported in ClinVar (Variation ID: 40503). Functional analyses show that this variant causes destabilization of the interdomain interface and in vitro phosphatase activity is altered (Bocchinfuso 2007). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.703). Additionally, other variants at this codon (Ala, Gly, Lys and Val) have been reported in individuals with Noonan syndrome or juvenile myelomonocytic leukemia and are considered disease-causing (Tartaglia 2001, Tartaglia 2003). Based on available information, this variant is considered to be pathogenic. References: Bocchinfuso G et al. Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2. Proteins. 2007 Mar 1;66(4):963-74. PMID: 17177198. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. English, Spanish. PMID: 31560489. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759. Tartaglia M et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID: 12717436.

Variant summary: The PTPN11 c.228G>C (p.Glu76Asp) variant involves the alteration of a conserved nucleotide located at the SH2 domain of the protein (InterPro, Keilhack _2005, Edouard_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 215446 control chromosomes (gnomAD). This variant has been reported in many individuals with NS (Tartaglia_2001, Aoki_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies showed variant with mild (2.5-3.1 fold) basal activation compared with WT (Keilhack _2005 and Niihori_2005). A variant involving the same nucleotide, c.228G>T, leading to the same codon change E76D, has been reported in affected individuals and was classified as pathogenic by our lab, suggesting the functional importance of this codon. Taken together, this variant is classified as pathogenic.

The Glu76Asp variant has been reported in at least 7 individuals with clinical f eatures of Noonan syndrome (Tartaglia 2006, Tartaglia 2001). Therefore, this var iant is highly likely to be pathogenic. The presence of a heterozygous pathogeni c variant in PTPN11 is consistent with a diagnosis of Noonan syndrome but this i nformation should be reconciled with the complete clinical history of this indiv idual.

The p.E76D pathogenic mutation (also known as c.228G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 228. The glutamic acid at codon 76 is replaced by aspartic acid, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Ferrero GB et al. Eur J Med Genet Jul;51:566-72). An alternate nucleotide change, c.228G>T, resulting in the same amino acid substitution p.E76D, has also been detected in Noonan syndrome cohorts (Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Functional studies have shown that p.E76D leads to increased phosphatase activity (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Keilhack H et al. J. Biol. Chem., 2005 Sep;280:30984-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.