Submissions for variant NM_002834.5(PTPN11):c.1052G>A (p.Arg351Gln)

dbSNP: rs397507534

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000521244	SCV000616450	benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.1052G>A (p.Arg351Gln) variant in the PTPN11 gene is 0.263% (55/16488) 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)
Eurofins Ntd Llc (ga)	RCV000373942	SCV000337430	uncertain significance	not provided	2015-11-25	criteria provided, single submitter	clinical testing
Invitae	RCV000521244	SCV001005886	likely benign	RASopathy	2024-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582506	SCV001821485	benign	not specified	2021-08-09	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1052G>A (p.Arg351Gln) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251446 control chromosomes. The observed variant frequency is approximately 6.81 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1052G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002399354	SCV002706617	benign	Cardiovascular phenotype	2019-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315540	SCV004017223	benign	Juvenile myelomonocytic leukemia	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541059	SCV004770278	benign	PTPN11-related disorder	2020-09-19	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).