Submissions for variant NM_002834.5(PTPN11):c.794G>T (p.Arg265Leu)

gnomAD frequency: 0.00003  dbSNP: rs376607329

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681121	SCV000808579	likely pathogenic	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Identified in a patient with dilated cardiomyopathy; segregation testing was not performed (AlHammouri HM et al 2024); 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: 11992261, 9491886, 16053901, 29493581, AlHammouri2024[Abstract])
Ambry Genetics	RCV002422462	SCV002676443	likely pathogenic	Cardiovascular phenotype	2024-05-17	criteria provided, single submitter	clinical testing	The p.R265L variant (also known as c.794G>T), located in coding exon 7 of the PTPN11 gene, results from a G to T substitution at nucleotide position 794. The arginine at codon 265 is replaced by leucine, an amino acid with dissimilar properties. Another variant at the same codon, p.R265Q, has been detected in multiple individuals with Noonan syndrome, including some de novo cases (van Trier DC et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jun;79:874-8; Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). Arginine 265 is located in the protein tyrosine phosphatase domain of the PTPN11 protein and forms ionic interaction with glutamate 76 in the SRC-2 homology 2 (N-SH2) domain (Darian E et al. Proteins, 2011 May;79:1573-88; Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002544702	SCV003239025	likely pathogenic	RASopathy	2022-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 265 of the PTPN11 protein (p.Arg265Leu). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg265 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27353043, 28074573). 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: 561741). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. This variant is not present in population databases (gnomAD no frequency).
PreventionGenetics, part of Exact Sciences	RCV004527734	SCV004111941	uncertain significance	PTPN11-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The PTPN11 c.794G>T variant is predicted to result in the amino acid substitution p.Arg265Leu. To our knowledge, this variant has not been reported in the literature. An alternate missense variant (p.Arg265Gln) has been well documented to be pathogenic and to affect protein function (Fokstuen et al. 2016. PubMed ID: 27353043; Pannone et al. 2017. PubMed ID: 28074573). This variant is reported in 0.00080% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/561741/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.