ClinVar Genomic variation as it relates to human health

Reported as a germline variant in patients with features of a Noonan spectrum disorder and myeloproliferative disease or leukemia (including JMML and AML), and in one patient with features of a Noonan spectrum disorder and Hodgkin's lymphoma (Tartgalia et al., 2003; Lo et al., 2008; Bluteau et al., 2018); Missense variants in this gene are often considered pathogenic (HGMD); 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: 19737548, 23334668, 16358218, 24754368, 29703613, 30355677, 30670449, 29037749, 26918529, 18758896, 30417923, 15001945, 22681964, 19077116, 27592337, 15928039, 29146883, 30050098, 29907801, 31560489, 33144682, 29493581, 33683002, 33318624, 34008892, 12960218, 12717436)

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 503 of the PTPN11 protein (p.Gly503Arg). This variant is present in population databases (rs397507545, gnomAD 0.004%). This missense change has been observed in individuals with Noonan syndrome or Leopard syndrome (PMID: 12717436, 12960218, 16358218, 18758896, 19077116, 19737548, 24754368). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40558). 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%. For these reasons, this variant has been classified as Pathogenic.

The p.Gly503Arg (due to c.1507G>C or c.1507G>A) variant has previously been repo rted >10 individuals with the clinical features of Noonan syndrome, including at least 2 de novo occurrences (Tartaglia 2003, Sarkozy 2003, Zenker 2004, Kratz 2 005, Lo 2008, Ezquieta 2012, LMM data). This variant has also been reported in i ndividuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML), JMM L, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Lo 2008). It ha s not been identified in large population studies. Three other variants involvin g this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as patho genic. Computational prediction tools and conservation analysis suggest that the p.Gly503Arg variant may impact the protein. In summary, this variant meets crit eria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4; PM1; PM2; PM6; PP3.

The p.G503R pathogenic mutation (also known as c.1507G>C), located in coding exon 13 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1507. The glycine at codon 503 is replaced by arginine, an amino acid with dissimilar properties, and is located in the PTP domain of the PTPN11 protein. This mutation has been reported in multiple individuals with Noonan syndrome, including at least two affected parent-child pairs (Sarkozy A et al. J Med Genet, 2003 Sep;40:704-8; Lo FS et al. Int J Hematol, 2008 Oct;88:287-290; Bessis D et al. Br J Dermatol, 2019 06;180:1438-1448). The same amino acid substitution caused by a different nucleotide change (c.1507G>A) has also been reported in individuals with Noonan syndrome (Tartaglia M et al. Am J Hum Genet, 2006 Feb;78:279-90; Athota JP et al. BMC Med Genet, 2020 03;21:50). There have been reports of a few individuals with p.G503R and Noonan syndrome diagnosed with juvenile myelomonocytic leukemia (JMML) (Strullu M et al. J Med Genet, 2014 Oct;51:689-97; Kratz CP et al. Br J Cancer, 2015 Apr;112:1392-7). In addition, other alterations at the same residue (p.G503A and p.G503E) have also been described in individuals with features of Noonan syndrome (Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Jongmans MC et al. Eur. J. Hum. Genet., 2011 Aug;19:870-4). Based on internal structural analysis, p.G503R is more destabilizing than other nearby pathogenic variants (Hof P et al. Cell, 1998 Feb;92:441-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Variant summary: PTPN11 c.1507G>C (p.Gly503Arg) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 252092 control chromosomes. c.1507G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions, including a father and daughter showing co-segregation with disease (e.g. Zenker_2004, Tartaglia_2006, Lo_2008, Pierpont_2009, Mathur_2014, Bessis_2019, Chinton_2019). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

PS1, PS4, PM5, PM6, PP2, PP3

PS1, PM1, PM2, PM5, PP2, PP3, PP5

The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040558,VCV000040559,VCV000571101, PMID:12960218,16358218, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040561, PMID:18678287,21407260,23756559, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992, 3CNET: 0.994, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

ACMG categories: PS1,PS4,PM6,PP3,PP4,PP5

The PTPN11 c.1507G>C; p.Gly503Arg variant (rs397507545) is reported in the literature in multiple individuals affected with Noonan syndrome and has been reported de novo in several (Chaves Rabelo 2022, Chinton 2019, Faggetter 2023, Hakami 2016, Matalon 2021, Mathus 2014, Sarkozy 2003). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.992). Based on available information, this variant is considered to be pathogenic. References: Chaves Rabelo N et al. RASopathy Cohort of Patients Enrolled in a Brazilian Reference Center for Rare Diseases: A Novel Familial LZTR1 Variant and Recurrent Mutations. Appl Clin Genet. 2022 Oct 21;15:153-170. PMID: 36304179. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. PMID: 31560489. Faggetter S et al. Hereditary spherocytosis associated with Noonan syndrome mimicking a dyserythropoietic anaemia. Pediatr Blood Cancer. 2023 Apr;70(4):e30121. PMID: 36579772. Hakami F et al. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn. 2016 May;36(5):418-23. PMID: 26918529. Matalon DR et al. Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies. Am J Med Genet A. 2021 May;185(5):1486-1493. PMID: 33683002. Mathur D et al. Twin infant with lymphatic dysplasia diagnosed with Noonan syndrome by molecular genetic testing. Fetal Pediatr Pathol. 2014 Aug;33(4):253-7. PMID: 24754368. Sarkozy A et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003 Sep;40(9):704-8. PMID: 12960218.

The PTPN11 c.1507G>C variant is predicted to result in the amino acid substitution p.Gly503Arg. This variant is located in a mutational hotspot region of the PTPN11 gene. It has been repeatedly reported to be causative for Noonan syndrome (Sarkozy et al. 2003. PubMed ID: 12960218; Holmfeldt et al. 2013. PubMed ID: 23334668; Chinton et al. 2019. PubMed ID: 31560489). Additionally, a different variant, 1507G>A, that results in the same amino acid change has been reported as causative for Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218). At PreventionGenetics, we previously detected the variant c.1507G>C in other affected patients. This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.