Submissions for variant NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly)

dbSNP: rs121918461

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000077856	SCV000057369	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	A published mouse model demonstrates that homozygous expression of the p(D61G) mutant is embryonic lethal, whereas heterozygotes have decreased viability and the surviving mice had features of Noonan syndrome and myeloproliferative disease, mimicking the human phenotype (Araki et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); Published functional studies demonstrate that p.(D61G) leads to enhanced basal activity of the protein compared to wild type (gain of function effect) (Keilhack et al., 2005); This variant is associated with the following publications: (PMID: 30355600, 30029678, 32164556, 19835954, 20651068, 24628801, 16377799, 19008228, 24718990, 27521173, 26242988, 24803665, 25383899, 22371576, 28328117, 28346493, 27924582, 11704759, 28366775, 28378436, 29659837, 30417923, 26918529, 30050098, 29907801, 31219622, 29146900, 31617209, 31324109, 33971972, 32981126, 32499374, 34006472, 11992261, 9491886, 16053901, 29493581, 15273746, 15987685)
Eurofins Ntd Llc (ga)	RCV000077856	SCV000058289	pathogenic	not provided	2013-03-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824738	SCV000199995	pathogenic	Juvenile myelomonocytic leukemia; Noonan syndrome	2015-07-14	criteria provided, single submitter	clinical testing	The p.Asp61Gly variant in PTPN11 has been previously reported in >30 individuals with Noonan syndrome with or without juvenile myelomonocytic leukemia (JMML) in cluding at least 5 de novo occurrences (Tartagila 2001, Kosaki 2002, Yoshida 200 4, Kratz 2005, Bertola 2006, Chan 2006, Shaw 2007, Noordam 2005, Strullu 2014, B ouchikhi 2015, LMM data). It was also identified as a somatic variant in 1 child with acute lymphoblastic leukemia (ALL) and 2 children with JMML (Yamamoto 2006 , Stullu 2014). It has not been identified in large population studies. Both in vivo animal models and in vitro studies provide evidence that this variant impac ts protein function (Araki 2004, Kontaridis 2006, Uhlen 2006, Eminaga 2008, Wang 2009, Xu 2010, De Rocca 2012, Bonetti 2014, Lee 2014). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome and JMML in an autosomal dominant manner.
Invitae	RCV000033464	SCV000549993	pathogenic	RASopathy	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 61 of the PTPN11 protein (p.Asp61Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and is one of the most commonly reported variants in this condition. It has also been observed in an individual with juvenile myelomonocytic leukemia. (PMID: 11704759, 11992261, 12634870, 15928039, 16358218, 17020470, 22420426, 23321623, 26084119, 26242988). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13330). 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: 15273746, 15987685, 16377799, 19008228). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626829	SCV000747532	pathogenic	Short stature; Abnormal cardiovascular system morphology	2017-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033464	SCV001338338	pathogenic	RASopathy	2020-02-29	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.182A>G (p.Asp61Gly) results in a non-conservative amino acid change located in the SH2 domain 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 251804 control chromosomes. c.182A>G has been well reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (example, Tartaglia_2001, Musante_2003, Bertola_2006, Kosaki_2002, Ferreira_2008, Strullu_2014). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function leading to activation of the Ras-ErK signaling pathway (example, Hu_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001270166	SCV001368980	pathogenic	LEOPARD syndrome 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000077856	SCV001446792	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000014258	SCV001572937	pathogenic	Noonan syndrome 1	2020-04-30	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV001376030	SCV001573042	pathogenic	Non-immune hydrops fetalis	2020-08-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077856	SCV001746164	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PTPN11: PS2, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813196	SCV002060828	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-07-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490363	SCV002795783	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-10-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147285	SCV003835273	pathogenic	Metachondromatosis	2022-06-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001270166	SCV003835292	pathogenic	LEOPARD syndrome 1	2022-06-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000014258	SCV003836330	pathogenic	Noonan syndrome 1	2022-06-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000014258	SCV004014682	pathogenic	Noonan syndrome 1	2022-12-20	criteria provided, single submitter	clinical testing	The PTPN11 c.182A>G (p.Asp61Gly) missense variant results in the substitution of asparagine at amino acid position 61 with glycine. This variant is one of the most commonvPTPN11 variants reported in association with Noonan syndrome. Across a selection of the available literature, the c.182A>G variant has been reported in at least 28 individuals with Noonan syndrome, at least six of whom also showed features of juvenile myelomonocytic leukemia or myeloproliferative disorder (PMID: 11992261; PMID: 15928039; PMID: 25097206; PMID: 26084119). The c.182A>G variant has also been shown to occur de novo in at least two additional affected individuals (PMID: 23321623; PMID: 26242988). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Structural modeling has shown that asparagine 61 is located at the N-SH2/PTP interaction surface, which is a mutational hotspot (PMID: 11992261), and functional assays have demonstrated that the variant enhances basal protein activity (gain of function) (PMID: 15987685). A heterozygous knock-in mouse model with the p.Asp61Gly amino acid change exhibits decreased viability and recapitulates clinical features of Noonan syndrome, including short stature, craniofacial anomalies, and myeloproliferative disease (PMID: 15273746). This variant was also identified in a de novo state. Based on the available evidence, the c.182A>G (p.Asp61Gly) variant is classified as pathogenic for Noonan syndrome.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000033464	SCV004123062	pathogenic	RASopathy	2023-07-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004532341	SCV004721419	pathogenic	PTPN11-related disorder	2024-02-28	criteria provided, single submitter	clinical testing	The PTPN11 c.182A>G variant is predicted to result in the amino acid substitution p.Asp61Gly. This variant has been repeatedly reported in individuals with Noonan syndrome and is one of the most common pathogenic variants in PTPN11 (see for example Tartaglia et al 2001. PubMed ID: 11704759). In at least two individuals it was reported as a de novo event (Croonen et al. 2013. PubMed ID: 23321623; Joyce et al. 2015. PubMed ID: 26242988). In vitro functional studies and knock-in mouse models are consistent with this variant disrupting normal protein function (Araki et al. 2004. PubMed ID: 15273746; Keilhack et al. 2005. PubMed ID: 15987685; Serra-Nédélec. 2012. PubMed ID: 22371576). This variant has been interpreted as pathogenic by multiple labs in ClinVar. Additionally, different amino acid substitutions (p.Asp61Asn, p.Asp61His, p.Asp61Ala) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Based on the available evidence, we interpret the PTPN11 c.182A>G (p.Asp61Gly) variant as pathogenic.
OMIM	RCV000014258	SCV000034506	pathogenic	Noonan syndrome 1	2002-08-01	no assertion criteria provided	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156984	SCV000206706	pathogenic	Noonan syndrome	2011-11-01	no assertion criteria provided	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000077856	SCV000207650	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000014258	SCV001482355	likely pathogenic	Noonan syndrome 1	2019-05-31	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000077856	SCV002035185	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000077856	SCV002037569	pathogenic	not provided		no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000014258	SCV003840155	pathogenic	Noonan syndrome 1		no assertion criteria provided	research
Molecular Genetics, Centre for Human Genetics	RCV000014258	SCV004190081	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing