Submissions for variant NM_002834.5(PTPN11):c.802G>T (p.Gly268Cys)

dbSNP: rs397507527

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033502	SCV000057407	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	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: 24803665, 16358218, 26785492, 21590266, 22465605, 28991257, 34008892, 32368696)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037660	SCV000061322	likely pathogenic	Noonan syndrome	2014-07-15	criteria provided, single submitter	clinical testing	The Gly268Cys variant in PTPN11 has been reported in two individuals with clinic al features of Noonan syndrome (Tartaglia 2006, LMM unpublished data), and is ab sent from large population studies. In addition, a second variant at this codon (Gly268Ser) has been identified in three affected individuals and segregated wit h disease in one of these individuals (Tartaglia 2006, Papadopoulou 2012), sugge sting that changes to this residue are not tolerated. Furthermore, glycine (Gly) at this position is highly conserved cross evolutionarily distant species and c omputational prediction tools suggest that the Gly268Cys variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the Gly268Cys variant is likely pathogenic.
Invitae	RCV000703823	SCV000832744	pathogenic	RASopathy	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 268 of the PTPN11 protein (p.Gly268Cys). This variant is present in population databases (rs397507527, gnomAD 0.006%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 16358218, 22465605, 26785492). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40523). 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. 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: 16358218, 21590266). 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265568	SCV001443727	pathogenic	PTPN11 Related Disorders	2019-10-30	criteria provided, single submitter	clinical testing	This variant has been previously reported in at least three patients with Noonan Syndrome (PMID: 16358218, 26785492, 22465605). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (1/241992) and thus is presumed to be rare. The c.802G>T (p.Gly268Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. ClinVar contains an entry for this variant (Variation ID: 40523). A different amino acid change at the same codon (p.Gly268Ser) has also been identified in individuals with Noonan Syndrome (PMID: 16358218, 26242988, 21590266). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.802G>T (p.Gly268Cys) variant is classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729355	SCV001976697	pathogenic	Noonan syndrome 1	2021-10-01	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3, PP5
Baylor Genetics	RCV003147308	SCV003834828	pathogenic	Metachondromatosis	2022-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001729355	SCV003835830	pathogenic	Noonan syndrome 1	2022-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147309	SCV003835901	pathogenic	LEOPARD syndrome 1	2022-12-12	criteria provided, single submitter	clinical testing