Submissions for variant NM_002834.5(PTPN11):c.558G>T (p.Arg186=)

gnomAD frequency: 0.00011  dbSNP: rs200920312

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000519311	SCV000616446	benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.558G>T (p.Arg186=) variant in the PTPN11 gene is 0.231% (49/16504) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154804	SCV000204484	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Arg186Arg in Exon 05 of PTPN11: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence. It has been identified in 1/3738 African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS;).
PreventionGenetics, part of Exact Sciences	RCV000154804	SCV000309213	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000154804	SCV000514319	benign	not specified	2015-07-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586177	SCV000698079	benign	not provided	2016-10-31	criteria provided, single submitter	clinical testing	Variant summary: The PTPN11 c.558G>T (p.Arg186Arg) variant causes a synonymous change involving a non-conserved nucleotide with 3/5 splice prediction tools predict no significant impact on normal splicing and no alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 60/121366 (1/2022, 1 homozygote), predominantly observed in the South Asian cohort, 49/16504 (1/336, 1 homozygote), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTPN11 variant of 1/16000. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. However, multiple clinical diagnostic laboratories/databases cite the variant as "likely benign." Therefore, the variant of interest has been classified as Benign.
Ambry Genetics	RCV000617423	SCV000740201	likely benign	Cardiovascular phenotype	2017-02-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Invitae	RCV000519311	SCV000776907	benign	RASopathy	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000154804	SCV001159460	benign	not specified	2019-05-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109479	SCV001266821	benign	Metachondromatosis	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001109480	SCV001266822	likely benign	Noonan syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001109481	SCV001266823	benign	LEOPARD syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813400	SCV002060596	likely benign	Noonan syndrome and Noonan-related syndrome	2020-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000154804	SCV002066638	likely benign	not specified	2020-05-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498744	SCV002809665	likely benign	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-04-25	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315942	SCV004017219	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586177	SCV004131966	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	PTPN11: BP4, BP7, BS1