Submissions for variant NM_002834.5(PTPN11):c.923A>C (p.Asn308Thr)

dbSNP: rs121918455

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033517	SCV000057422	pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing	Identified in patients with cystic hygroma and other abnormal ultrasound findings in published literature (Wilbe et al., 2017; Lee et al., 2009); 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: 18759865, 29057136, 15001945, 24803665, 28921562, 28991257, 19077116, 33318624, 32978145, 32368696, 11992261, 9491886, 16053901, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037668	SCV000061330	pathogenic	Noonan syndrome	2016-09-12	criteria provided, single submitter	clinical testing	The p.Asn308Thr variant has been reported in 7 individuals with clinical feature s of Noonan syndrome (Tartaglia 2006, Pierpont 2009, LMM data) and was absent fr om large population studies. Computational prediction tools and conservation ana lysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, two amino aci d changes at this position (p.Asn308Ser, p.Asn308Asp) are well established patho genic variants for Noonan syndrome further suggesting that a change at this posi tion may not be tolerated. In summary, this variant meets our criteria to be cla ssified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon frequency in probands and absence from controls.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000037668	SCV000884433	pathogenic	Noonan syndrome	2017-08-14	criteria provided, single submitter	clinical testing	The PTPN11 c.923A>C;p.Asn308Thr variant has been described in several individuals with a clinical diagnosis of Noonan syndrome (Ndiaye 2014, Pierpont 2009, Tartaglia 2006). The variant is listed in the ClinVar database (Variation ID: 40535) and the dbSNP variant database (rs121918455) but not described in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Ndiaye R et al. Mutation N308T of protein tyrosine phosphatase SHP-2in two Senegalese patients with Noonan syndrome. J Med Genet Gen. 2014 6(1): 6-10. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193110	SCV001361726	pathogenic	RASopathy	2019-10-22	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.923A>C (p.Asn308Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase (IPR000242) 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 251440 control chromosomes (gnomAD). c.923A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Tartaglia_2006, Lee_2008, Pierpont_2009, Wilbe_2017). These data indicate that the variant is very likely to be associated with disease. In addition, other variants at the same codon have been reported to be associated with Noonan Syndrome, indicating it as a hotspot. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193110	SCV001587259	pathogenic	RASopathy	2022-01-15	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn308 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 19077116, 21340158; s16358218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 40535). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 28921562, 28991257). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 308 of the PTPN11 protein (p.Asn308Thr).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813251	SCV002060449	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002287350	SCV002577919	pathogenic	See cases	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PM2,PM7,PP3,PP5
Ambry Genetics	RCV002371807	SCV002687610	pathogenic	Cardiovascular phenotype	2015-09-13	criteria provided, single submitter	clinical testing	The p.N308T pathogenic mutation (also known as c.923A>C), located in coding exon 8 of the PTPN11 gene, results from an A to C substitution at nucleotide position 923. The asparagine at codon 308 is replaced by threonine, an amino acid with similar properties. In one study, this mutation was detected in an individual with a clinical diagnosis of Noonan syndrome (Pierpont EI, et al. Genes Brain Behav. 2009;8(3):275-82). This mutation was also described in two individuals who likely had clinical diagnoses of either Noonan syndrome or Leigus syndrome; however, clinical diagnoses were not confirmed (Tartaglia M et al. Am J Hum Genet. 2006; 78(2):279-290). The Asn308 residue has been presented as a mutational hot spot, and two different mutations located in this same residue, p.N308S and p.N308D, have been described in multiple individuals with Noonan syndrome (Qiu W, et al. BMC Struct. Biol. 2014;14():10); Tartaglia M, et al. Nat. Genet. 2001;29(4):465-8; Zenker M, et al. J. Pediatr. 2004;144(3):368-74). Based on the supporting evidence, p.N308T is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002482942	SCV002781259	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-03-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000033517	SCV004131969	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PTPN11: PS2, PM2, PM5, PP3, PS4:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000033517	SCV004226878	pathogenic	not provided	2023-04-14	criteria provided, single submitter	clinical testing	PP2, PP3, PM1, PM2_supporting, PS2, PS4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV004668747	SCV005093822	pathogenic	Noonan syndrome 1	2024-08-05	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795947	SCV005418654	pathogenic	LEOPARD syndrome 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PP3_Strong+PM5_Strong+PP2
PreventionGenetics, part of Exact Sciences	RCV004532491	SCV004733870	pathogenic	PTPN11-related disorder	2024-01-17	no assertion criteria provided	clinical testing	The PTPN11 c.923A>C variant is predicted to result in the amino acid substitution p.Asn308Thr. This variant has been reported in at least four individuals with Noonan syndrome (Tartaglia et al. 2005. PubMed ID: 16358218; Pierpont et al. 2008. PubMed ID: 19077116; Table S9 - Jin et al. 2017. PubMed ID: 28991257). Additionally, this variant has been reported in three affected fetuses with features consistent with Noonan syndrome (Lee et al. 2008. PubMed ID: 18759865; Wilbe et al. 2017. PubMed ID: 28921562). Both de novo inheritance and gonadal mosaicism have been documented (Wilbe et al. 2017. PubMed ID: 28921562; Table S9 - Jin et al. 2017. PubMed ID: 28991257). This variant has not been reported in a large population database, indicating this variant is rare. Different amino acid substitutions (p.Asn308Asp and p.Asn308Ser) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). This variant is interpreted as pathogenic.