Submissions for variant NM_002834.5(PTPN11):c.1471C>G (p.Pro491Ala)

dbSNP: rs397507539

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159056	SCV000208998	pathogenic	not provided	2024-09-12	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32737134, 28650561, 31292302, 28607217)
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV001002766	SCV000992409	pathogenic	Noonan syndrome 1		criteria provided, single submitter	case-control
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813411	SCV002060835	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2017-11-05	criteria provided, single submitter	clinical testing	This missense variant results in a change from proline to alanine at amino acid position 491. This variant has been reported in an individual with PTPN11-associated Noonan syndrome and occurred de novo (PMID: 32737134). Different amino acid changes impact this position have been reported in individuals with PTPN11-related disorders (PMID: 15985475, 18470943, 20186801, 22781091, 23624134). This variant is observed at an allele frequency of 0.00019% in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as pathogenic (PS2, PM2, PM5, PP3, PP5).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515083	SCV003264397	pathogenic	RASopathy	2022-03-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 18470943, 20186801, 22781091, 23624134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 32737134). 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: 181503). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 28650561, 32737134). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 491 of the PTPN11 protein (p.Pro491Ala).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003764999	SCV004697350	pathogenic	Astrocytic tumor	2024-02-21	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261020	SCV001438417	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing