ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.925A>G (p.Ile309Val) (rs201787206)

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Total submissions: 13
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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,Partners HealthCare 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 Other strong data supporting benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000151704 SCV000343780 likely benign not specified 2016-07-27 criteria provided, single submitter clinical testing
Invitae RCV000470114 SCV000560644 likely benign Rasopathy 2020-10-26 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 Clinical Genomics Lab, 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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

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