Submissions for variant NM_002834.5(PTPN11):c.846C>G (p.Ile282Met)

dbSNP: rs397507530

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033506	SCV000057411	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21934682, 23917401, 25742478, 26817465, 31560489, 34006472)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037661	SCV000061323	likely pathogenic	Noonan syndrome	2018-12-21	criteria provided, single submitter	clinical testing	The p.Ile282Met variant in PTPN11 has been reported in 3 individuals with clinic al features of Noonan syndrome and was inherited from an affected parent in one of these cases (Atik 2016, Klapecki 2005, LMM unpublished data). This variant wa s absent from large population studies. It has been reported in ClinVar (Variat ion ID 40526) and has been reported as a somatic variant in a glioblastoma (Frat tini 2013). Computational prediction tools and conservation analysis suggest th at this variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. Furthermore, another variant at this positi on (p.Ile282Val) has been reported in multiple individuals with clinical feature s of Noonan syndrome and is classified as pathogenic by our laboratory and in Cl inVar (Variation ID 40525). In summary, although additional studies are required to fully establish its clinical significance, the p.Ile282Met variant is likely pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: P M2, PM5, PP3, PS4_Supporting.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001027860	SCV001190494	likely pathogenic	Noonan syndrome 1	2019-12-18	criteria provided, single submitter	research	ACMG codes: PS4M, PM2, PP3, PP5
DASA	RCV001027860	SCV002061174	pathogenic	Noonan syndrome 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.846C>G;p.(Ile282Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40526; PMID: 26817465; 23917401) - PS4.This variant is not present in population databases (rs397507530, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 40525) - PM5. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Invitae	RCV001852676	SCV002235812	pathogenic	RASopathy	2022-10-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile282 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 15834506, 19077116, 21407260). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40526). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26817465, 31560489, 34006472). 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 isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 282 of the PTPN11 protein (p.Ile282Met).
CeGaT Center for Human Genetics Tuebingen	RCV000033506	SCV002497636	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	PTPN11: PM1, PM2, PS2:Moderate, PS4:Moderate, PP2, PP3
Ambry Genetics	RCV002444454	SCV002680620	likely pathogenic	Cardiovascular phenotype	2020-08-10	criteria provided, single submitter	clinical testing	The p.I282M variant (also known as c.846C>G), located in coding exon 7 of the PTPN11 gene, results from a C to G substitution at nucleotide position 846. The isoleucine at codon 282 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in subjects who have a phenotype consistent with Noonan syndrome (Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Kruszka P et al. Am. J. Med. Genet. A, 2017 Sep;173:2323-2334; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337; Castellanos E et al. Clin. Genet., 2020 02;97:264-275; Ambry internal data). A different amino acid substitution at the same position, p.I282V, has been documented in two unrelated individuals with Noonan syndrome (Tartaglia M, et al. Nat. Genet. 2001;29(4):465-8. Jongmans MC, et al. Eur. J. Hum. Genet. 2011;19(8):870-4). This variant was not reported in population-based 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 majority of available evidence to date, this variant is likely to be pathogenic.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000037661	SCV001438413	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV001027860	SCV001482357	pathogenic	Noonan syndrome 1	2019-05-31	no assertion criteria provided	research