Submissions for variant NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala)

dbSNP: rs121918469

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000077850	SCV000057436	pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing	Reported in association with Noonan syndrome with multiple lentigines (NSML and formerly called LEOPARD syndrome) and Noonan syndrome (Sarkozy et al., 2004; Ko et al., 2008; Ferrero et al., 2008); Published functional studies demonstrate expression of this variant results in reduced catalytic activity (Kontaridis et al., 2006; Yu et al., 2014); 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: 17453145, 16804314, 24935154, 24718990, 16377799, 24790373, 25937001, 19020799, 15121796, 18678287, 27484170, 27666661, 16358218, 15389709, 30105547, 29263817, 30896080, 29602897, 33318624, 32746448, 29493581)
Eurofins Ntd Llc (ga)	RCV000077850	SCV000058282	pathogenic	not provided	2013-03-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824746	SCV000203928	pathogenic	Noonan syndrome with multiple lentigines; Noonan syndrome	2014-03-04	criteria provided, single submitter	clinical testing	The p.Gly464Ala variant in PTPN11 has been reported in at least 2 individuals wi th clinical features of Noonan syndrome or LEOPARD syndrome (Ko 2008, Ferrero 20 08, Kitsiou-Tzeli 2006). In addition, this variant has been identified by our la boratory in 2 individuals with clinical features of a Noonan spectrum disorder. It was absent from large population studies. Furthermore, functional studies sug gest this variant has a dominant negative effect, which is an established pathog enic mechanism in LEOPARD syndrome (Kontaridis 2006, Edouard 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan or LEO PARD syndrome in an autosomal dominant manner (http://www.partners.org/personali zedmedicine/LMM).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000077850	SCV000281117	pathogenic	not provided	2014-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV000033531	SCV000549989	pathogenic	RASopathy	2024-01-11	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 464 of the PTPN11 protein (p.Gly464Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LEOPARD syndrome and Noonan syndrome (PMID: 15121796, 15389709, 16358218, 18678287, 19020799, 25937001). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13343). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 24935154). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001281363	SCV001468660	pathogenic	Noonan syndrome 1	2020-11-02	criteria provided, single submitter	research	ACMG codes:PS4, PS1, PM2, PP5
Mayo Clinic Laboratories, Mayo Clinic	RCV000077850	SCV001714429	pathogenic	not provided	2020-10-28	criteria provided, single submitter	clinical testing	PS4, PS2, PM6, PM2, PP2, PP3
Revvity Omics, Revvity	RCV000077850	SCV002019558	pathogenic	not provided	2020-04-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813203	SCV002060462	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-06-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077850	SCV002063070	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001281363	SCV002577534	pathogenic	Noonan syndrome 1	2022-01-18	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP2, PP3, PP5
Ambry Genetics	RCV002390105	SCV002696141	pathogenic	Cardiovascular phenotype	2022-01-03	criteria provided, single submitter	clinical testing	The p.G464A pathogenic mutation (also known as c.1391G>C), located in coding exon 12 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1391. The glycine at codon 464 is replaced by alanine, an amino acid with similar properties. This mutation was identified in multiple individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome), including at least three reportedly de novo cases (Sarkozy A et al. J. Med. Genet., 2004 May;41:e68; Yoshida R et al. Am. J. Med. Genet. A, 2004 Nov;130A:432-4; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Willig LK et al. Lancet Respir Med, 2015 May;3:377-87; Noll AC et al. NPJ Genom Med, 2016 Aug;1:16026; Nakagama Y et al. Circ Heart Fail, 2018 Apr;11:e004660). In addition, functional analyses demonstrated that this mutation has a dominant negative effect and causes conformational changes in the protein structure (Kontaridis MI et al. J. Biol. Chem., 2006 Mar;281:6785-92; Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV001281363	SCV002761721	pathogenic	Noonan syndrome 1	2022-06-30	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000033531	SCV004034108	pathogenic	RASopathy	2023-07-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000077850	SCV004564603	pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	The PTPN11 c.1391G>C; p.Gly464Ala variant (rs121918469) is reported in the literature in multiple individuals and families with LEOPARD syndrome and Noonan syndrome (Baldo 2022, Nakagama 2018, Sarkozy 20004, Willig 2015). This variant is also reported in ClinVar (Variation ID: 13343). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.985). In support of these predictions, functional studies demonstrate that the variant protein has reduced catalytic activity compared to wildtype (Kontaridis 2006, Yu 2014). Based on available information, this variant is considered to be pathogenic. References: Baldo F et al. New insights on Noonan syndrome's clinical phenotype: a single center retrospective study. BMC Pediatr. 2022 Dec 24;22(1):734. PMID: 36566191. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. PMID: 16377799. Nakagama Y et al. Accelerated Cardiomyocyte Proliferation in the Heart of a Neonate With LEOPARD Syndrome-Associated Fatal Cardiomyopathy. Circ Heart Fail. 2018 Apr;11(4):e004660. PMID: 29602897. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. PMID: 15121796. Willig LK et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015 May;3(5):377-87. PMID: 25937001. Yu ZH et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014 Jul 1;53(25):4136-51. PMID: 24935154.
PreventionGenetics, part of Exact Sciences	RCV003924834	SCV004737634	pathogenic	PTPN11-related condition	2024-02-02	criteria provided, single submitter	clinical testing	The PTPN11 c.1391G>C variant is predicted to result in the amino acid substitution p.Gly464Ala. This variant is well documented to be causative in patients with Noonan syndrome with or without multiple lentigines (Sarkozy et al. 2004. PubMed ID: 15121796; Willig et al. 2015. PubMed ID: 25937001; Yu et al. 2019. PubMed ID: 30896080; Yoshida et al. 2004. PubMed ID: 15389709; Tartaglia et al. 2005. PubMed ID: 16358218; Ferrero et al. 2008. PubMed ID: 18678287; Ko et al. 2008. PubMed ID: 19020799). Consistent with other PTPN11 variants that cause Noonan syndrome with multiple lentigines, functional studies found this variant results in a loss of catalytic activity that results in a dominant negative effect (Kontaridis et al. 2006. PubMed ID: 16377799; Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000055883	SCV000034520	pathogenic	LEOPARD syndrome 1	2004-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000055883	SCV000086889	not provided	LEOPARD syndrome 1		no assertion provided	literature only