Submissions for variant NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly)

dbSNP: rs121918454

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157679	SCV000057378	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased activation of ERK1/2 (Sun et al., 2018); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15956085, 12960218, 34241941, 34728626, 11992261, 15928039, 19020799, 11704759, 24803665, 30355600, 30541462, 30417923, 26918529, 29907801, 31219622, 31560489, 32164556, 9491886, 16053901, 29493581, 29568093, 31785789)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157006	SCV000199999	pathogenic	Noonan syndrome	2018-03-20	criteria provided, single submitter	clinical testing	The p.Ala72Gly variant in PTPN11 has been previously identified in >10 individua ls with clinical features of Noonan syndrome (Tartaglia 2001, Sarkozy 2003, Ferr eira 2005, Kratz 2005, Ko 2008, LMM data) and 1 individual with Noonan syndrome and myeloproliferative disorder (Kratz 2005). This variant was reported to have occurred de novo in at least four of these individuals (Ferreira 2005, LMM data) . It was absent from large population studies. This variant has also been report ed in ClinVar (Variation ID 13325). Several other variants involving this codon (p.Ala72Pro, p.Ala72Thr, p.Ala72Ser, p.Ala72Val) have been reported as pathogen ic. In summary, this variant meets criteria to be classified as pathogenic for N oonan in an autosomal dominant manner based upon case observations, de novo occu rrences, presence of other pathogenic variants at this codon, and absence from c ontrols. ACMG/AMP Criteria applied: PS4; PM5_Strong; PM6_Strong; PM2.
Fulgent Genetics, Fulgent Genetics	RCV000515213	SCV000611304	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	RCV000587329	SCV000698071	pathogenic	Noonan syndrome 3	2017-03-11	criteria provided, single submitter	clinical testing	Variant summary: The PTPN11 c.215C>G (p.Ala72Gly) variant involves the alteration of a highly conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The Ala72 codon is located within the N-SH domain and interacts directly with PTP domain residue Glu506. Although p.Ala72Gly has not been tested in functional studies, other alterations of this codon, p.Ala72Val and p.Ala72Ser, were shown to promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway (Tartaglia, 2006). The variant is absent from control datasets of ExAC and gnomAD (121394 chrs and 245816 chrs tested, respectively), however was reported in multiple affected individuals with clinically confirmed dx of NS and NSRD (Tartaglia, 2001; Tartaglia, 2006, Sarkozy, 2003 and Ezquieta, 2012) including several de novo events. The codon Ala72 appears to be a mutational hot-spot, as other alteration, such as p.A72P, p.A72V, p.A72S have been reported in patients with NS and NSRD. In addition, multiple reputable databases/clinical laboratories cite the variant as Pathogenic. Taking together, the variant of interest was classified as Pathogenic.
Invitae	RCV000707460	SCV000836559	pathogenic	RASopathy	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala72 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 12161469, 14974085, 16399795, 17339163, 18678287, 26918529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 13325). This missense change has been observed in individual(s) with Noonan syndrome and hypertrophic cardiomyopathy and mitral valve anomaly (PMID: 11704759, 12960218, 15001945, 15956085, 19020799). 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 alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 72 of the PTPN11 protein (p.Ala72Gly).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000157006	SCV000897638	pathogenic	Noonan syndrome	2019-03-29	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157679	SCV000927961	pathogenic	not provided	2018-09-28	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000014253	SCV001190490	likely pathogenic	Noonan syndrome 1	2020-01-21	criteria provided, single submitter	research	ACMG codes: PS4M, PM2, PP3, PP5
CeGaT Center for Human Genetics Tuebingen	RCV000157679	SCV001246729	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000014253	SCV001522575	pathogenic	Noonan syndrome 1	2020-02-20	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000157679	SCV001714423	pathogenic	not provided	2019-04-22	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM6_Strong, PP2, PP3
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813191	SCV002060917	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-05-05	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000014253	SCV002556848	pathogenic	Noonan syndrome 1	2022-04-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426502	SCV002727256	pathogenic	Cardiovascular phenotype	2018-06-11	criteria provided, single submitter	clinical testing	The p.A72G pathogenic mutation (also known as c.215C>G), located in coding exon 3 of the PTPN11 gene, results from a C to G substitution at nucleotide position 215. The alanine at codon 72 is replaced by glycine, an amino acid with similar properties. This mutation is located between the SH2 and PTP domains of PTPN11 and been detected in several individuals with clinically diagnosed Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ko JM et al. J. Hum. Genet., 2008 Dec;53:999-1006), one of which was a de novo occurrence; however, paternity was not confirmed (Ferreira LV et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5156-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000014253	SCV004012905	pathogenic	Noonan syndrome 1	2023-07-14	criteria provided, single submitter	clinical testing
OMIM	RCV000014253	SCV000034501	pathogenic	Noonan syndrome 1	2001-12-01	no assertion criteria provided	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157006	SCV000206732	pathogenic	Noonan syndrome	2012-10-22	no assertion criteria provided	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157679	SCV000207653	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000014253	SCV003840151	pathogenic	Noonan syndrome 1		no assertion criteria provided	research