Submissions for variant NM_002834.5(PTPN11):c.802G>A (p.Gly268Ser)

dbSNP: rs397507527

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037659	SCV000061321	likely pathogenic	Noonan syndrome	2015-09-29	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000159050	SCV000208992	likely pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 26203125, 32164556, 26242988, 24803665, 25722345, 12717436, 21590266, 18470943, 16358218)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587886	SCV000698080	pathogenic	RASopathy	2023-05-03	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.802G>A (p.Gly268Ser) results in a non-conservative amino acid change located in the tyrosine-specific protein phosphatase, PTPase domain (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247722 control chromosomes (gnomAD and Tartaglia_2006). c.802G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome, and co-segregated with disease in at least one family (e.g. Tartaglia_2006, Joyce_2015, Athota_2020, Papadopoulos_2022). 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. However, a variant affecting the same amino acid (p.Gly268Cys) has also been classified as likely pathogenic/pathogenic by multiple clinical laboratories (via ClinVar), suggesting that the p.Gly268 residue is important for PTPN11 function. The following publications have been ascertained in the context of this evaluation (PMID: 24803665, 25722345, 32164556, 26242988, 35904599, 16358218, 12717436). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001330780	SCV001522577	pathogenic	LEOPARD syndrome 1	2019-09-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000587886	SCV001592599	pathogenic	RASopathy	2022-08-31	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with Noonan syndrome (PMID: 21590266, 26242988, 32164556). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 268 of the PTPN11 protein (p.Gly268Ser). ClinVar contains an entry for this variant (Variation ID: 44614). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly268 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22465605, 26785492). 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.
Blueprint Genetics	RCV000159050	SCV001832514	likely pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159050	SCV002019556	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415470	SCV002681155	likely pathogenic	Cardiovascular phenotype	2023-11-30	criteria provided, single submitter	clinical testing	The p.G268S variant (also known as c.802G>A), located in coding exon 7 of the PTPN11 gene, results from a G to A substitution at nucleotide position 802. The glycine at codon 268 is replaced by serine, an amino acid with similar properties. This alteration has been detected in individuals with Noonan syndrome phenotypes (Joyce S et al. Eur. J. Hum. Genet., 2016 May;24:690-6; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Papadopoulou A et al. Eur. J. Pediatr., 2012 Jan;171:51-8; Liu G et al. Sci Rep, 2017 10;7:13262). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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.
Fulgent Genetics, Fulgent Genetics	RCV002504894	SCV002808244	likely pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-09-13	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338391	SCV004047382	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing	The missense variant c.802G>A (p.Gly268Ser) in PTPN11 gene has been reported in heterozygous state in individual affected with Noonan syndrome 1 (Athota JP, Bhat M, Nampoothiri S, et al., 2020). This variant disrupts the p.Gly268 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (Homsy J et al., 2015). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. The p.Gly268Ser variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic and Likely Pathogenic. The amino acid Gly at position 268 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly268Ser in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003338391	SCV004244470	likely pathogenic	Noonan syndrome 1	2023-11-07	criteria provided, single submitter	clinical testing	PS4, PP2, PP3
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159050	SCV001979627	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000159050	SCV001980552	pathogenic	not provided		no assertion criteria provided	clinical testing