Submissions for variant NM_002834.5(PTPN11):c.174C>G (p.Asn58Lys)

dbSNP: rs397507506

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033457	SCV000057362	pathogenic	not provided	2024-09-23	criteria provided, single submitter	clinical testing	Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; Not observed at significant frequency 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: 22190897, 26607044, 32164556, 12634870, 23321623, 25914815, 24803665, 28425981, 16358218, 15928039, 20954246, 15723289, 18286234, 30417923, 30050098, 29907801, 35979676, 11992261, 9491886, 16053901, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211846	SCV000061292	pathogenic	Noonan syndrome	2022-11-22	criteria provided, single submitter	clinical testing	The c.174C>G, p.Asn58Lys variant in PTPN11 has been reported in at least 6 individuals with clinical features of Noonan syndrome and segregated with disease in at least 4 affected relatives from one family (Musant 2003 PMID:12634870, Tartaglia 2006 PMID:16358218, Derbent 2010 PMID:20954246, Digilio 2011 PMID:22190897, Croonen 2013 PMID:23321623, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 40489) and absent from large population studies. Computational tools and conservation analyses are consistent with pathogenicity. Another variant resulting in the same missense change (c.172A>C, p.Asn58His) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have also been reported in ClinVar as a Pathogenic variant by several clinical laboratories, including this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PS4, PP1, PM2_Supporting, PM5_strong, PP3.
UCLA Clinical Genomics Center, UCLA	RCV000037630	SCV000255445	likely pathogenic	Noonan syndrome 1	2012-12-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515267	SCV000611302	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2017-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588173	SCV000698063	pathogenic	RASopathy	2017-04-03	criteria provided, single submitter	clinical testing	Variant summary: The PTPN11 c.174C>G (p.Asn58Lys) variant located in the mutational hotspot, SH2 domain, involves the alteration of a non-conserved nucleotide and by 4/4 in-silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 122184 control chromosomes including broad and large populations from ExAC. Publications have cited this variant as a pathogenic variant and has been detected in several patients with Noonans syndrome, including multiple instances of a de novo origin (Musante_2003, Tartaglia_2006, Derbent_2010, Digilio_2011, Ezquieta_2012, Croonen_2012, Coromilas_2015, and Cizmarova_2015). Other missense variants at this residue (N58Y, N58D, N58H, and N58S) are reported in association with Noonan syndrome and are classified as pathogenic/likely pathogenic by submitters in ClinVar, strongly suggesting that the codon itself is a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000211846	SCV000746841	pathogenic	Noonan syndrome	2017-12-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000033457	SCV001246726	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588173	SCV001392879	pathogenic	RASopathy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 12634870, 20954246, 22190897, 23321623). ClinVar contains an entry for this variant (Variation ID: 40489). 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%. 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, 16263833, 19125092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.