ClinVar Genomic variation as it relates to human health

The Ser502Leu variant has been reported in the literature in two individuals wit h clinical features of Noonan syndrome and/or LEOPARD syndrome (Tartaglia 2006, Ko 2008). Our laboratory has identified this variant in one proband where parent al testing was performed and showed the variant occurred de novo (LMM unpublishe d data). This variant has also been identified as a somatic variant in individua ls with hematologic malignancies including AML and ALL (Goemans 2005, Paulsson 2 007). In addition, three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Ala) have been associated with the clinical features of Noonan syndrome and have also been identified as somatic variants in individuals with h ematologic malignancies (Aoki 2008). The Ser502 residue is conserved across spec ies and computational analyses (biochemical amino acid properties, AlignGVGD, Po lyPhen2, and SIFT) suggest that the Ser502Leu variant may impact the normal func tion of the protein. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon the de novo occurrenc e combined with available published literature.

Variant summary: PTPN11 c.1505C>T (p.Ser502Leu) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, there are several variants associated with disease at the same codon or surrounding codons (e.g., S502A, S502T, R501K, and G503A), suggesting the region is important for protein function. Serine at position 502 interacts with Glutamate at position 76 in the SH2 domain, leading to autoinhibition of PTPN11, and mutational hotspot variants at Serine 502 or Glutamate 76 were shown to activate PTPN11 (example, Chan_2007, PMID 17053061). The variant was absent in 252092 control chromosomes. c.1505C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (example, Tartaglia_2006, Bertola_2006, Ezquieta_2012, Strullu_2014, Ko_2008, O'Halloran_2017). At-least one report of a reportedly de-novo occurrence was ascertained in the context of this evaluation (Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 28628100, 28084675, 24030381, 18948947, 17910045, 15385933, 28183348, 26918529, 18470943, 17020470, 16358218, 19020799, 24803665, 28991257, 30050098, 30287924, 29907801, 32164556, 31115076, 33318624, 29493581, 32368696)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser502 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12325025, 15928039, 18470943, 23832011, 26242988, 27521173). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 40557). This missense change has been observed in individuals with Noonan syndrome or LEOPARD syndrome (PMID: 17020470, 19020799). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 502 of the PTPN11 protein (p.Ser502Leu).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0251 - This variant is heterozygous. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Both the p.(Ser502Ala) and the p.(Ser502Thr) have been previously reported in patients with Noonan syndrome (ClinVar, PMID: 18470943, PMID: 11992261). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Noonan syndrome (ClinVar, PMID: 18470943, PMID: 11992261, PMID: 28084675 and PMID: 32164556). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) by trio analysis. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PTPN11: PS2:Very Strong, PM2, PM5, PP3

This variant c.1505C>T(p.S502L) has been reported in multiple unrelated pateints with Noonan spectrum disorders [PMID: 22465605, 17020470, 32164556, 26918529, 28991257, 24803665, 29907801, 15385933, 30287924] and was reported to be de novo in at least one case (PS2). Missense variants in the same residue and nearby residues have been reported in multiple individuals with Noonan spectrum disorders (PMID: 16358218, 26242988, 23832011) (PM1). This variant is currently absent in the gnomAD database (PM2). Computational evidence support a deleterious effect on the gene product (PP3). This variant has been classified as pathogenic by multiple labs in ClinVar [Variation ID: 40557] (PP5). This variant is interpreted as pathogenic according to ACMG/AMP guidelines.