Submissions for variant NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala)

dbSNP: rs397507509

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033461	SCV000057366	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Reported in unrelated individuals with JMML in published literature (Loh et al., 2004; Kratz et al., 2005); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21407260, 16643459, 17020470, 24803665, 29493581, 16053901, 9491886, 11992261, 8328949, 24039098, 18562489, 16263833, 14644997, 18328949, 27521173, 17053061, 26817465, 17546245, 30417923, 28607217, 28328117, 26918529, 31560489, 32164556, 15928039, 34643321, 33318624, 32737134)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037631	SCV000061293	pathogenic	Noonan syndrome	2015-07-09	criteria provided, single submitter	clinical testing	The p.Gly60Ala variant has been reported in >20 individuals with clinical featur es of Noonan syndrome (Tartaglia 2002, Binder 2005, Bertola 2006, Limal 2006, Ta rtaglia 2006, Roti 2006, Mutesa 2008, Noordam 2008, Jongmans 2011, Ross 2014, LM M unpublished data) but not identified in large population studies. This variant occurred de novo in at least one of the affected individuals (Roti 2006). In ad dition, this variant has been reported in two individuals with clinical features of Noonan syndrome and a central nervous system tumor (neuroblastoma, Mutesa 20 08; dysembryoplastic neuroepithelia tumor, Jongmans 2011) and as a somatic chang e in AML (Loh 2004). In summary, this variant meets our criteria to be classifie d as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals, de novo occurrence, and absence from control s.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000416546	SCV000494452	pathogenic	Noonan syndrome 1	2016-06-08	criteria provided, single submitter	clinical testing
Invitae	RCV000459297	SCV000549986	pathogenic	RASopathy	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 60 of the PTPN11 protein (p.Gly60Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 11992261, 16643459, 17020470, 18328949, 24039098, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40493). 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%. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000416546	SCV000782247	pathogenic	Noonan syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000416546	SCV000992390	pathogenic	Noonan syndrome 1		criteria provided, single submitter	case-control
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813244	SCV002060773	pathogenic	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
3billion	RCV000416546	SCV002573168	pathogenic	Noonan syndrome 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040493 ) and different missense changes at the same codon (p.Gly60Arg, p.Gly60Asp, p.Gly60Cys, p.Gly60Ser, p.Gly60Val/ ClinVar ID: VCV000040490, VCV000041442, VCV000055797, VCV000372590, VCV000987743) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002408494	SCV002717286	pathogenic	Cardiovascular phenotype	2017-11-22	criteria provided, single submitter	clinical testing	The p.G60A pathogenic mutation (also known as c.179G>C), located in coding exon 3 of the PTPN11 gene, results from a G to C substitution at nucleotide position 179. The glycine at codon 60 is replaced by alanine, an amino acid with similar properties. This mutation was in multiple individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Bertola DR et al. Genet. Test., 2006;10:186-91; Jongmans MC et al. Eur. J. Hum. Genet., 2011 Aug;19:870-4; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21). In addition, this variant is located in the NSH2 domain, which interacts with the PTP domain to regulate switching of the resulting protein between its inactive and active conformations (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000416546	SCV002768018	pathogenic	Noonan syndrome 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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 (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 21533187, 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0701 - Many other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many alternative missense changes have been reported in multiple individuals with Noonan syndrome 1 (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the well reported pathogenic variants causes Noonan syndrome (ClinVar, PMID: 32164556). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000033461	SCV003826738	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000416546	SCV004100519	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing	The missense c.179G>Cp.Gly60Ala has been reported in heterozygous state in individuals affected with Noonan syndrome Athota JP, et. al., 2020. Experimental studies indicates that this variant is expected to disrupt PTPN11 function Tartaglia M, et. al.,2002. The p.Gly60Ala variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The amino acid change p.Gly60Ala in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 60 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000033461	SCV001932134	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000033461	SCV001951331	pathogenic	not provided		no assertion criteria provided	clinical testing