ClinVar Genomic variation as it relates to human health

PP3, PS1, PM5, PP2, PS4, PM2_SUP

The PTPN11 c.854T>C variant is predicted to result in the amino acid substitution p.Phe285Ser. This variant has been reported in at least four unrelated individuals with Noonan syndrome (Tartaglia et al. 2002. PubMed ID: 11992261; Yoshida et al. 2004. PubMed ID: 15240615; Ko et al. 2008. PubMed ID: 19020799; Essawi et al. 2013. PubMed ID: 24183200), two fetal cases suggestive of Noonan syndrome (Croonen et al. 2013. PubMed ID: 23321623; Normand. 2018. PubMed ID: 30266093), and in a case of syndromic juvenile myelomonocitic leukemia (JMML) (Prontera et al. 2011. PubMed ID: 21106241). In at least three of these cases the variant was likely de novo (Prontera et al. 2011. PubMed ID: 21106241; Croonen et al. 2013. PubMed ID: 23321623; Normand. 2018. PubMed ID: 30266093). Functional studies demonstrate the p.Phe285Ser leads to an increase in basal PTPN11 activity and increased sensitivity to ligand stimulation (LaRochelle et al. 2016. PubMed ID: 27030275). Additionally, different amino acid substitutions affecting the same amino acid (p.Phe285Leu, p.Phe285Cys) have been reported in individuals with Noonan syndrome (Human Gene Mutation Database). At PreventionGenetics, we previously identified this variant in other individuals with Noonan syndrome. This variant has been interpreted as pathogenic by multiple clinical labs in ClinVar. This variant is interpreted as pathogenic.

The p.Phe285Ser variant in PTPN11 has been reported in the literature in several individuals with the clinical features of Noonan syndrome, and has been shown to have arisen as a de novo event in some of these individuals (Aoki 2008, Tartaglia 2006, Kosaki 2002, Park 2012, Essawi 2013, LMM data). This variant was absent from large population studies. In addition, several other amino acid changes at this position (p.Phe285Cys, p.Phe285Leu) have also been reported in individuals with Noonan spectrum features. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP codes applied: PS4, PM2, PM5_Strong, PM6_Strong.

Variant summary: PTPN11 c.854T>C (p.Phe285Ser) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246952 control chromosomes (gnomAD). The variant, c.854T>C, has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Tartaglia_2006, Kosaki_2002, Croonen_2013, Lee_2011, ssawi_2013, Bertola_2006, Prontera_2013). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. In addition, other missense mutations at this position, Phe285Cys and Phe285Leu, have been reported to be pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published X-ray crystallography studies showed the variant causes conformational changes, and functional in vitro studies demonstrated modestly increased basal phosphatase activity; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21901340, 30266093, 11992261, 24183200, 21106241, 24803665, 29907801, 12161469, 26918529, 30732632, 30050098, 31219622, 27030275, 32164556, 32668031)

The PTPN11 c.854T>C variant is a single nucleotide change in exon 8/16 of the PTPN11 gene, which is predicted to change the amino acid phenylalanine at position 285 in the protein to serine. This variant has been identified as a de novo variant in this fetus (PS2). The variant has been reported in 12 probands with a clinical presentation of Noonan Syndrome (e.g. PMID: 11992261; PMID:24183200) (PS4). This variant is absent from population databases (PM2). This is a missense variant in a constrained region of the PTPN11 gene, where missense variants are a common mechanism of disease and benign variation is rare (PP2). This variant is a missense change at an amino acid residue where many different missense changes have been seen before, and associated with disease (e.g. PMID: 23321623) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs121918463) and in the HGMD database: CM021134. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 13335).

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013335 / PMID: 11992261 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Phe285Cys, p.Phe285Ile, p.Phe285Leu, p.Phe285Tyr, p.Phe285Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040527, VCV000040528, VCV000040533, VCV000044615, VCV000181499, VCV000636408, VCV001201246 / PMID: 11992261, 16358218, 17339163, 18678287, 30896080 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This variant has been previously reported as a de novo change in patients with Noonan Syndrome (PMID: 11992261, 18470943, 24183200, 19020799, 15240615,23321623, 21106241 ). Different amino acid changes at the same residue (p.Phe285Cys, p.Phe285Leu) have been previously reported in individuals with Noonan Syndrome (PMID: 16358218, 18470943, 11992261). The PTPN11 gene is highly constrained (Z-score= 3.13 and pLI = 1), which suggests it is intolerant to variation. It was illustrated that the c.854T>C (p.Phe285Ser) variant increases PTPN11 basal activity and sensitivity to ligand stimulation (PMID: 27030275). The c.854T>C (p.Phe285Ser) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.854T>C (p.Phe285Ser) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.854T>C (p.Phe285Ser) variant is classified as Pathogenic.

PP2, PP3, PM2, PM6_strong, PS3_supporting, PS4

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the PTPN11 protein (p.Phe285Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 15240615, 18470943, 19020799, 21106241, 23321623, 24183200). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13335). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 27030275). This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 16358218, 18470943). 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.

PTPN11: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP3

Activating PTPN11 mutation found in ETP-ALL, juvenile myelomonocytic leukemia, and Noonan syndrome