ClinVar Genomic variation as it relates to human health

Reported previously in a patient with Noonan syndrome; however further clinical details and information about parental testing was not provided (PMID: 15001945); 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18470943, 22681964, 24803665, 16053901, 24150203, 15001945, 31827275, 34358384, 16358218, 22465605)

A heterozygous missense variant, NM_002834.3(PTPN11):c.329A>C, has been identified in exon 3 of 16 of the PTPN11 gene. The variant is predicted to result in an amino acid change from glutamic acid to alanine at position 110 of the protein (NP_002825.3(PTPN11):p.(Glu110Ala)). The glutamic acid residue at this position hasvery high conservation (100 vertebrates, UCSC), and is located within the Linker region that connects the N-SH2 and C-SH2 functional domains. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in individuals with Noonan syndrome (ClinVar, Zenker et al., (2004)). A different variant in the same codon resulting in a change to lysine has also been reported to cause Noonan syndrome and the variant was shown to be de novo (ClinVar, Ezquieta et al., (2012)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.

Variant summary: PTPN11 c.329A>C (p.Glu110Ala) results in a non-conservative amino acid change located in the linker region that connects the N-SH2 and C-SH2 functional domains (Tartaglia_2006) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251352 control chromosomes (gnomAD and publication). c.329A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome or Pulmonary valve stenosis (Zenker_2004, Tartaglia_2006, Digilio_2012, Downie_2019). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue, E110K, was found in individuals affected with Noonan Syndrome (HGMD), suggesting that this variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

The PTPN11 c.329A>C; p.Glu110Ala variant (rs397507519) is reported in the literature in several individuals affected with Noonan syndrome or a related RASopathy (Tartaglia 2006, Zenker 2004). 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 a single laboratory in ClinVar (Variation ID: 40508). The glutamate at codon 110 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant occurs in the linker between the N- and C-terminal SH2 domains, and it is predicted to influence the orientation or mobility of these domains (Tartaglia 2006). Additionally, another variant at this amino acid (p.Glu110Lys) has been reported in several individuals with Noonan syndrome or another RASopathy (Ezquieta 2012, Rodriguez 2014). Based on available information, the p.Glu110Ala variant is considered to be likely pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. Rodriguez FA et al. Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome. J Pediatr Endocrinol Metab. 2014 Mar;27(3-4):305-9. 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. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 Mar;144(3):368-74.

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 110 of the PTPN11 protein (p.Glu110Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RASopathy spectrum disorders and/or Noonan syndrome (PMID: 15001945; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Glu110 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22465605, 24150203, 24451042; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.