ClinVar Genomic variation as it relates to human health

proposed classification - variant undergoing re-assessment, contact laboratory

This variant has been previously reported in several individuals with PTPN11-related disorders (PMID: 14961557, 15928039, 22528600, 30732632, 31219622, 32164556), and it was a de novo change in at least three patients (PMID: 30732632). In-vitro functional assessment of this alteration revealed that it affects the normal phosphatase activity of the protein (PMID: 15987685, 24935154, 24628801). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1529A>C (p.Gln510Pro) 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.1529A>C (p.Gln510Pro) variant is classified as Pathogenic.

Published functional studies demonstrate p.(Q506P) affects the catalytic phosphatase domain (PTP) of the protein and interferes with its normal phosphatase activity (Qiu et al., 2014; Yu et. al, 2014); The majority of missense variants in this gene are considered pathogenic (HGMD); Located in the critical PTP functional domain and mutational hotspot region (Yu et al. 2014); 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: 15121796, 15928039, 16358218, 22528600, 24628801, 14961557, 30508783, 32164556, 14644997, 15987685, 26742426, 24803665, 18470943, 15723289, 20954246, 20301557, 30732632, 31219622, 33240318, 24935154)

Variant summary: PTPN11 c.1517A>C (p.Gln506Pro) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.1517A>C has been reported in the literature in individuals affected with Noonan Syndrome including de novo occurrences (Kratz_2005, Willig_2015, Li_2019, Athota_2020). These data indicate that the variant is likely to be associated with disease. Functional studies report this variant exhibits reduced catalytic activity (Yu_2014, Qiu_2014). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987685; 24935154; 26742426) - PS3.The c.1517A>C;p.(Gln506Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40563; PMID: 18470943; PMID: 14961557; PMID: 15723289; PMID: 15928039; PMID: 20954246; PMID: 22528600) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Y_phosphatase) - PM1. This variant is not present in population databases (rs397507548- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 506 of the PTPN11 protein (p.Gln506Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome or Noonan syndrome with multiple lentigines, some of whom also had a myeloproliferative disorder (PMID: 14961557, 15723289, 15928039, 18470943, 20954246, 22528600). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40563). 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: 15987685, 24935154, 26742426). For these reasons, this variant has been classified as Pathogenic.

The p.Q506P pathogenic mutation (also known as c.1517A>C), located in coding exon 13 of the PTPN11 gene, results from an A to C substitution at nucleotide position 1517. The glutamine at codon 506 is replaced by proline, an amino acid with similar properties. This mutation was first described as a de novo occurrence, paternity not confirmed, in a patient with a clinical diagnosis of Noonan syndrome with multiple lentigines (NSML, referred to as LEOPARD syndrome) including findings of mild hypertelorism, pulmonic stenosis, unilateral sensorineural hearing loss, and mild cognitive impairment (Conti E et al. Hum. Mutat., 2003 Jun;21:654). It has subsequently been reported in additional patients with Noonan syndrome or NSML (Derbent M et al. Am. J. Med. Genet. A, 2010 Nov;152A:2768-74; Piard J et al. Am. J. Med. Genet. A, 2012 Jun;158A:1406-10). Structural and functional studies indicate that this mutation results in a weakened auto-inhibited enzyme conformation leading to prolonged substrate turnover, producing a gain-of-function rasopathy phenotype through sustained activation of the RAS-ERK pathway (Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The c.1517A>C is a known pathogenic variant that has been reported in multiple unrelated individuals with Noonan spectrum disorders [PMID: 14961557, 15121796,15928039, 15723289, 20954246, 22528600]. This variant is reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID:40563). The c.1517A>C variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1517A>C variant is located in exon 13 of this 16-exon gene and is predicted to replace an evolutionarily conserved glutamine amino acid with proline at position 506 in the protein-tyrosine phosphatase domain of the encoded protein [PMID: 24628801]. In silico predictions are in favor of damaging effect for p.(Gln506Pro) variant [(CADD v1.6 = 32, REVEL = 0.9)]. Published functional studies have shown reduced catalytic phosphatase activity of protein carrying the p.(Gln506Pro) variant [PMID: 15987685, 24628801, 24935154, 26742426]. Based on available evidence this de novo c.1517A>C p.(Gln506Pro) variant identified in PTPN11 is classified as Pathogenic.

The PTPN11 c.1517A>C variant is predicted to result in the amino acid substitution p.Gln506Pro. This variant has been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (see for example - Conti et al. 2003. PubMed ID: 14961557; Athota et al. 2020. PubMed ID: 32164556) and in several of the individuals it was found to be de novo (see for example - Chen et al. 2019. PubMed ID: 30732632). Functional and structural studies found this variant inhibits catalytic activity (Keilhack et al. 2005. PubMed ID: 15987685; Qiu et al. 2014. PubMed ID: 24628801; Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

The c.1517A>C missense variant in PTPN11 is absent from population databases like gnomAD, indicating rarity (PM2). It was not observed in other affected family members. In silico predictions (SIFT: 0.001) suggest a damaging effect (PP3), and the variant affects a conserved region of the protein (PM1). Based on these factors, the variant is classified as likely pathogenic (ACMG codes: PM1, PM2, PP3, PP5).