Submissions for variant NM_002834.5(PTPN11):c.1746C>T (p.Asn582=)

gnomAD frequency: 0.00013  dbSNP: rs397516800

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037628	SCV000061290	benign	not specified	2015-04-07	criteria provided, single submitter	clinical testing	p.Asn582Asn in exon 15 of PTPN11: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 4/15702 South As ian chromosomes and 8/63828 European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516800 ). Furthermore, it has been identified by our laboratory in an unaffected mother and 2 individuals with features of Noonan syndrome, one of which also carried another variant in PTPN11 sufficient to explain their disease.
PreventionGenetics, part of Exact Sciences	RCV000037628	SCV000309205	likely benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000546916	SCV000659039	likely benign	RASopathy	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619648	SCV000740265	likely benign	Cardiovascular phenotype	2017-12-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037628	SCV001362748	benign	not specified	2019-06-10	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1746C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 250916 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1746C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001689592	SCV001911682	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496597	SCV002807778	likely benign	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-12-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001689592	SCV003917246	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PTPN11: BP4, BP7