Submissions for variant NM_002834.5(PTPN11):c.1529A>G (p.Gln510Arg)

dbSNP: rs121918470

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414743	SCV000490887	pathogenic	not provided	2023-07-20	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28125078, 35248088, 33318624, 30050098, 26817465, 29290338, 30919686, 24150203, 22465605, 24939587, 32737134, 15948193, 23312806, 29907801, 35586607, 35352813, 34704406, 24775816)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780654	SCV000918107	likely pathogenic	RASopathy	2019-09-30	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1529A>G (p.Gln510Arg) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Other alterations of codon Q510 have been reported in patients with NS, LEOPARD syndrome, and ALL (Q510K, Q510E, Q510P-Aoki_PTPN11_HM_2008, PMID: 18470943) indicating Q510 is a mutational hotspot. The variant allele was found at a frequency of 4e-06 in 251892 control chromosomes. c.1529A>G has been reported in the literature in individuals affected with features of Neurofibromatosis/Noonan syndrome (Bertola_2005), LEOPARD syndrome (Carcavilla_2013), megalencephaly-capillary malformation syndrome (MCAP) (Docker_2015), suspected/diagnosed Noonan syndrome (Ezquieta_2012, Atik_2016), and one case report of Ewing sarcoma (Brohl_2017). The variant was reported as a de-novo occurrence in at-least two of these studies although the presenting phenotype was MCAP (with paternity confirmed) in one and NS (assumed paternity due to lack of traceable evidence) in the other (Docker_2015, Atik_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, until additional reports of its presence in individuals diagnosed with Noonan syndrome and/or experimental evidence demonstrating an impact on function are reported, the variant was classified as likely pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV001002770	SCV000992415	pathogenic	LEOPARD syndrome 1		criteria provided, single submitter	case-control
CeGaT Center for Human Genetics Tuebingen	RCV000414743	SCV001247475	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000414743	SCV001474185	pathogenic	not provided	2019-09-25	criteria provided, single submitter	clinical testing	The PTPN11 c.1529A>G; p.Gln510Arg variant (rs121918470), is reported in the literature in multiple individuals affected with Noonan syndrome or LEOPARD syndrome (Atik 2016, Bertola 2005, Carcavilla 2013). Additionally, in testing performed at ARUP Laboratories, this variant has been observed in at least one other individual with symptoms of a RASopathy. This variant is found on a single chromosome (1/251492 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamine at codon 510 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Glu, His, and Pro) have been reported in individuals with Noonan syndrome or LEOPARD syndrome and are considered pathogenic (Chen 2019, Gezdirici 2017, Keren 2004, Wakabayashi 2011). Based on available information, the p.Gln510Arg variant is considered to be pathogenic. References: Atik T et al. Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations. Indian J Pediatr. 2016 Jun;83(6):517-21. Bertola DR et al. Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A. 2005 Jul 30;136(3):242-5. Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. Chen H et al. Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort. Orphanet J Rare Dis. 2019 Feb 7;14(1):29. Gezdirici A et al. How necessary is to analyze PTPN11 gene in fetuses with first trimester cystic hygroma and normal karyotype? J Matern Fetal Neonatal Med. 2017 Apr;30(8):938-941. Keren B et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004 Nov;41(11):e117. Wakabayashi Y et al. Implantable cardioverter defibrillator for progressive hypertrophic cardiomyopathy in a patient with LEOPARD syndrome and a novel PTPN11 mutation Gln510His. Am J Med Genet A. 2011 Oct;155A(10):2529-33.
Invitae	RCV000780654	SCV002212544	pathogenic	RASopathy	2023-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 510 of the PTPN11 protein (p.Gln510Arg). This variant is present in population databases (rs121918470, gnomAD 0.003%). This missense change has been observed in individuals with PTPN11-related conditions (PMID: 15948193, 24775816). ClinVar contains an entry for this variant (Variation ID: 13345). 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. This variant disrupts the p.Gln510 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15520399, 15690106, 19582499). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014273	SCV002766811	pathogenic	Noonan syndrome 1	2022-02-02	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, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene associated with Noonan syndrome are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated tyrosine-protein phosphatase domain (UniProt). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative change to histidine and proline at the position, have been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel and have multiple pathogenic entries in ClinVar. Additionally, de novo changes to glutamic acid and leucine have been reported in two cardiomyopathy probands (VCGS) and in a Noonan syndrome proband (ClinVar), respectively. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with Noonan syndrome, Noonan syndrome with multiple lentigines, and in an individual with Neurofibromatosis-Noonan syndrome who also harboured a variant in the NF1 gene (PMID: 26817465, 24775816, 15948193, ClinVar). This variant has also been identified in an individual with restrictive cardiomyopathy and features of rasopathy who also harboured a variant in FLNC gene (PMID: 30919686). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion	RCV000014273	SCV003841463	pathogenic	Noonan syndrome 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant 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: 0.96; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000013345) and different missense changes at the same codon (p.Gln510Glu, p.Gln510His, p.Gln510Leu, p.Gln510Pro / ClinVar ID: VCV000013344, VCV000040566, VCV000040567, VCV000811634, VCV000981537) 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	RCV004018624	SCV005020097	pathogenic	Cardiovascular phenotype	2024-02-08	criteria provided, single submitter	clinical testing	The p.Q510R pathogenic mutation (also known as c.1529A>G), located in coding exon 13 of the PTPN11 gene, results from an A to G substitution at nucleotide position 1529. The glutamine at codon 510 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in Noonan syndrome cohorts and individuals with concerns for PTPN11-related RASopathy where this alteration arose de novo with some of those individuals also having a dual diagnosis (Bertola DR et al. Am J Med Genet A, 2005 Jul;136:242-5; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Carcavilla A et al. Rev Esp Cardiol (Engl Ed), 2013 May;66:350-6; D&ouml;cker D et al. Eur J Hum Genet, 2015 Mar;23:409-12; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Rold&aacute;n-Sevilla A et al. Circ Genom Precis Med, 2019 Mar;12:e002388; Mutai H et al. Orphanet J Rare Dis, 2022 Mar;17:114; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261). Two other alterations at the same codon, p.Q510H (c.1530G>C) and p.Q510E (c.1528C>G), have been detected in multiple individuals with PTPN11-related RASopathy (Takahashi K et al. Eur. J. Pediatr. 2005;164:497-500; Wakabayashi Y et al. Am. J. Med. Genet. A, 2011 Oct;155A:2529-33; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29; Chinton J et al. Arch Argent Pediatr, 2019 Oct;117:330-337; Kauffman H et al. Pediatr Res, 2021 Aug;90:444-451). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is unclear.
OMIM	RCV000014273	SCV000034522	pathogenic	Noonan syndrome 1	2005-07-30	no assertion criteria provided	literature only