Submissions for variant NM_002834.5(PTPN11):c.781C>T (p.Leu261Phe)

gnomAD frequency: 0.00003  dbSNP: rs397507525

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000522926	SCV000616414	pathogenic	RASopathy	2017-04-03	reviewed by expert panel	curation	The c.781C>T (p.Leu261Phe) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 22465605; GeneDx, Cave lab internal data ClinVar SCV000057404.12). The p.Leu261Phe variant has also been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; SCV000061319.5, SCV000207687.1 PMID: 22465605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PM1, PP2.
GeneDx	RCV000157701	SCV000057404	pathogenic	not provided	2022-11-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significantly increased ERK phosphorylation activity (Pannone et al., 2017); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22465605, 30417923, 31130284, 22494877, 27311873, 28074573, 11992261, 9491886, 16053901, 29493581, 33354767)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037657	SCV000061319	pathogenic	Noonan syndrome	2015-09-29	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000522926	SCV000951642	pathogenic	RASopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 261 of the PTPN11 protein (p.Leu261Phe). This variant is present in population databases (rs397507525, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 22465605, 28074573). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40520). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 28074573). This variant disrupts the p.Leu261 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22253195, 23756559, 28074573). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000157701	SCV001905581	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496500	SCV002810522	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-11-11	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000522926	SCV004800978	pathogenic	RASopathy	2024-03-13	criteria provided, single submitter	curation	The heterozygous p.Leu261Phe variant in PTPN11 was identified by our study in one individual with Duane retraction syndrome, abnormality of the masticatory muscle, ventricular septal defect, choanal atresia, solitary median maxillary central incisor, enlarged joints, scoliosis, panhypopituitarism, syringomyelia, episodic pain, and hand tremor, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). We believe this is a phenotype expansion for PTPN11-related RASopathies. The p.Leu261Phe variant in PTPN11 has been previously reported in at least 11 unrelated individuals with PTPN11-related RASopathies (PMID: 33354767, PMID: 28074573, PMID: 31130284, PMID: 30417923, PMID: 22494877, PMID: 22465605) and segregated with disease in 3 affected relatives from 1 family (PMID: 33354767), but has been identified in 0.0015% (1/68022) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs397507525). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population for diseases with clinical variability or reduced penetrance. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 6 individuals with confirmed paternity and maternity (PMID: 28074573, PMID: 31130284, PMID: 22465605). This variant has also been reported in ClinVar (Variation ID: 40520) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. The p.Leu261Phe variant is located in a region of PTPN11 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 29493581). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Leu261His, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 28074573, 22253195, 23756559; Variation ID: 575203). The number of missense variants reported in PTPN11 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PTPN11-related rasopathies. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM1, PM5_Supporting, PP2 (Richards 2015).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157701	SCV000207687	likely pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing