Submissions for variant NM_002834.5(PTPN11):c.172A>C (p.Asn58His)

dbSNP: rs397507505

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157676	SCV000057359	pathogenic	not provided	2017-11-22	criteria provided, single submitter	clinical testing	The N58H missense variants in the PTPN11 gene has been reported previously in association with autosomal dominant Noonan syndrome (Limal et al., 2006). The N58H variant lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations. The N58H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037626	SCV000061288	pathogenic	Noonan syndrome	2015-10-23	criteria provided, single submitter	clinical testing	The p.Asn58His variant in PTPN11 has been previously identified in at least 8 in dividuals with clinical features of Noonan syndrome or Cardio-facio-cutaneous sy ndrome, including two reportedly de novo occurrences (Tartaglia 2006, Limal 2006 , Ezquieta 2012, Bertelloni 2013, LMM unpublished data). It was absent from larg e population studies. In addition, two different amino acid changes at this posi tion (Asn58Asp, Asn58Lys) has also been reported in individuals with clinical fe atures of Noonan syndrome (Mustante 2003, Zenker 2004, Tartaglia 2006, Sherman 2 009, Digilio 2011, Coromilas 2015). Computational prediction tools and conservat ion analysis suggest that this variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, this var iant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner (http://pcpgmwww.partners.org/personalizedmedicince/L MM) based upon segregation studies and absence from controls.
Eurofins Ntd Llc (ga)	RCV000157676	SCV000340585	pathogenic	not provided	2016-03-21	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000157676	SCV000511378	pathogenic	not provided	2016-09-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456871	SCV000549997	pathogenic	RASopathy	2022-07-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15001945, 15956085, 19125092). 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: 40486). This missense change has been observed in individuals with Noonan syndrome (PMID: 16263833, 16358218, 21204800, 23624134, 23756559). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000456871	SCV001774647	pathogenic	RASopathy	2021-07-19	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.172A>C (p.Asn58His) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251000 control chromosomes (gnomAD). c.172A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2005, Limal_2006, Bertelloni_2013, Hakami_2016, Bessis_2019, Li_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants at the same codon (N58D, N58K, N58I) have been classified as pathogenic by our laboratory indicating the asparagine residue is critical for the protein function. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV000037626	SCV002318975	pathogenic	Noonan syndrome	2022-03-25	criteria provided, single submitter	clinical testing	The c.172A>C;p.(Asn58His) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 40486; PMID:22465605; PMID:33128510; PMID:16263833; PMID:16358218; PMID:23624134; PMID:26918529)- PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2 domain; PMID: 20301303) - PM1. Pathogenic missense variant in this residue have been reported (Clinvar ID: 40487; PMID: 26918529; 15001945; 22465605) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 22465605) - PM6. 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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470725	SCV002769147	pathogenic	Noonan syndrome 1	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, 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 and LEOPARD syndrome have been associated with a loss of function, whereas Noonan syndrome is caused by gain of function variants (OMIM). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to histidine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (10 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (SH2 domain; PDB, Decipher). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple alternative changes at the same residue, to tyrosine, aspartic acid and lysine, have previously been reported as pathogenic in multiple patients with Noonan syndrome (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with Noonan syndrome (PMID: 16263833, ClinVar). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157676	SCV004562567	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	The PTPN11 c.172A>C; p.Asn58His variant (rs397507505) is reported in the literature in several individuals with Noonan syndrome (Hakami 2016, Kiel 2014, Li 2019, Limal 2006). This variant is also reported in ClinVar (Variation ID: 40486). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.76). Additionally, the variant is located in the N-SH2 domain of PTPN11 (Hof 1998), and other variants at this residue have been implicated in Noonan syndrome (Tartaglia 2006). Based on available information, the p.Asn58His variant is considered to be pathogenic. References: 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. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886. Kiel C et al. Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Mol Syst Biol. 2014 May 6;10(5):727. PMID: 24803665. Limal JM et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006 Jan;91(1):300-6. PMID: 16263833. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157676	SCV000207647	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000037626	SCV000805099	pathogenic	Noonan syndrome	2016-06-07	no assertion criteria provided	clinical testing