Submissions for variant NM_002834.5(PTPN11):c.925A>G (p.Ile309Val)

gnomAD frequency: 0.00026  dbSNP: rs201787206

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000470114	SCV000616415	benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The filtering allele frequency of the c.925A>G (p.Ile309Val) variant in the PTPN11 gene is 0.04% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (46/66736 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).
GeneDx	RCV000589645	SCV000057424	benign	not provided	2016-06-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151704	SCV000200021	benign	not specified	2017-10-10	criteria provided, single submitter	clinical testing	p.Ile309Val in exon 8 of PTPN11: This variant is not expected to have clinical s ignificance because it has been identified in 1% (103/10152) of Ashkenazi Jewish chromosomes, including 1 homozygous individual, by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201787206). Furthermore, the p.Ile307Val variant has been identified in at least 2 unaffected individuals (Tartaglia 2002, LMM data). ACMG/AMP Criteria applied: BA1, BS2 (Richards 2015) .
Ambry Genetics	RCV000252493	SCV000319157	likely benign	Cardiovascular phenotype	2018-09-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000151704	SCV000343780	likely benign	not specified	2016-07-27	criteria provided, single submitter	clinical testing
Invitae	RCV000470114	SCV000560644	likely benign	RASopathy	2024-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589645	SCV000698087	likely benign	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The PTPN11 c.925A>G (p.Ile309Val) variant involves the alteration of a conserved nucleotide and affected amino acid (Ile309) is located in the Protein-tyrosine phosphatase(PTP)-like domain. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 50/121802 control chromosomes (1 homozygote) at a frequency of 0.0004105, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in NS patients and at least one unaffected parent, suggesting this variant may not be associated with the disease. In addition, one clinical diagnostic laboratory classified this variant as likely benign and provided following description: "this variant has been identified in 3/80 (3.8%) of Ashkenazi-Jewish control chromosomes (Dr. Bruce Gelb, LMM personal communication), suggesting that this variant is a common polymorphism in this population." Taken together, this variant is classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761037	SCV000890952	benign	Noonan syndrome	2020-09-30	criteria provided, single submitter	clinical testing	The c.925A>G missense variant has a frequency of 0.0004596 (130 of 282,830) in gnomAD v2.1.1 with a maximal allele frequency of 0.01003 (104 of 10,370) in the Ashkenazi Jewish subpopulation including one homozygote (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581; SCV000616415.3). Although five of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), these predictions have not been confirmed by functional studies. In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1.
Mendelics	RCV000988916	SCV001138829	benign	Metachondromatosis	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000988916	SCV001269371	benign	Metachondromatosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001111780	SCV001269372	benign	LEOPARD syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001111781	SCV001269373	uncertain significance	Noonan syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000151704	SCV001433387	likely benign	not specified	2019-11-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813252	SCV002060597	benign	Noonan syndrome and Noonan-related syndrome	2020-09-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000151704	SCV002068604	benign	not specified	2019-02-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964830	SCV004780113	benign	PTPN11-related condition	2019-09-09	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).