ClinVar Genomic variation as it relates to human health

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2 of the PTPN11 protein (p.Thr2Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12960218, 19449407, 25337068, 25862627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13349). 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%. For these reasons, this variant has been classified as Pathogenic.

Variant summary: PTPN11 c.5C>T (p.Thr2Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 113882 control chromosomes (gnomAD and literature). c.5C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (Sarkozy_2003, Thiel_2009, Tartaglia_2006, Louati_2014, vanTrier_2015, Pierpont_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no 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 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Thr2Ile variant in PTPN11 has been identified in 6 individuals with clinic al features of Noonan syndrome (Sarkozy 2003, Tartaglia 2006, Thiel 2009, Louati 2014, LMM unpublished data), and was reported to have occurred de novo in 2 of these individuals (Thiel 2009, Louati 2014). Data from large population studies is insufficient to assess the frequency of this variant (dbSNP rs267606990). In summary, this variant meets our criteria to be classified as pathogenic for Noon an syndrome in an autosomal dominant manner based upon de novo occurrences.

DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.5C>T, in exon 1 that results in an amino acid change, p.Thr2Ile. This sequence change has not been described in population databases gnomAD, ExAC). The p.Thr2Ile change has been reported in several individuals with Noonan syndrome. In two of these individuals, this sequence change was reported to be de novo (PMIDs: 12960218, 19449407, 25337068, 25862627). The p.Thr2Ile change affects a moderately conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. The p.Thr2Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Pathogenic missense variants in the PTPN11 gene are predominantly missense in nature. This sequence change likely causes a disease phenotype, however functional studies have not been performed to prove this conclusively.

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: 0.21; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013349). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19449407,25337068,25862627). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 16358218, 30050098, 29907801, 12960218, 20186801, 25862627, 19449407, 32963807, 25337068)

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, and have been associated with metachondromatosis (MIM#156250) and Noonan syndrome 1 (MIM#163950), respectively (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in individuals with Noonan syndrome. One individual was also reported with a high grade glioma (ClinVar, PMID: 30693642). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2

Variant classified as Pathogenic and reported on 12-12-2018 by UCLA Laboratory Genetics and Genomics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.