Submissions for variant NM_002834.5(PTPN11):c.1502G>A (p.Arg501Lys)

dbSNP: rs397507543

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033541	SCV000057446	pathogenic	not provided	2022-04-19	criteria provided, single submitter	clinical testing	Identified in several unrelated patients with Noonan syndrome in published literature (Tartaglia et al., 2002; Limal et al., 2006; Noordam et al., 2008; Jefferies et al., 2010); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19795160, 24803665, 18562489, 11992261, 16263833, 18470943, 31134136, 33726816, 35325944)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037618	SCV000061280	pathogenic	Noonan syndrome	2016-01-26	criteria provided, single submitter	clinical testing	The p.Arg501Lys variant in PTPN11 has been reported in >10 individuals with the clinical features of Noonan syndrome and segregated with disease in 1 affected r elative (Tartaglia 2002, Limal 2006, Noordam 2008, Jefferies 2010, LMM unpublish ed data). It has not been identified in large population studies. In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon presence in multiple affected indivi duals, segregation studies, and absence in the general population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466382	SCV000549998	pathogenic	RASopathy	2023-07-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 40555). This missense change has been observed in individuals with Noonan syndrome (PMID: 11992261, 16263833, 18470943, 18562489, 19795160). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 501 of the PTPN11 protein (p.Arg501Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000466382	SCV001554571	pathogenic	RASopathy	2021-03-25	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1502G>A (p.Arg501Lys) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.1502G>A has been widely reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2002, Limal_2006, Aoki_2008, Noordam_2008, Jefferies_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000033541	SCV001714430	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing	PP2, PP3, PM2_supporting, PS4
Institute of Human Genetics, University Hospital Muenster	RCV001800333	SCV002047380	pathogenic	Epicanthus; Short stature; Abnormal cardiovascular system morphology; Abnormal pinna morphology; Wide nasal bridge; Microcephaly; Depressed nasal ridge	2021-12-13	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,PP4,PP5
Ambry Genetics	RCV004018716	SCV003745277	pathogenic	Cardiovascular phenotype	2021-10-05	criteria provided, single submitter	clinical testing	The c.1502G>A (p.R501K) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a G to A substitution at nucleotide position 1502, causing the arginine (R) at amino acid position 501 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple patients with Noonan syndrome (Tartaglia, 2002; Limal, 2006; Noordam, 2008; Jefferies, 2010; Moniez, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV002260947	SCV005387924	likely pathogenic	Noonan syndrome 1	2024-06-18	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795949	SCV005417653	likely pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1		criteria provided, single submitter	clinical testing	PS4_Moderate+PS2_Supporting+PM2_Supporting+PP2+PP3+PP4
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000033541	SCV001977744	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000033541	SCV001978659	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000033541	SCV001979338	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Genetics, Beijing BioBiggen Technology Co., Ltd.	RCV002260947	SCV002540760	pathogenic	Noonan syndrome 1	2022-06-29	no assertion criteria provided	research