ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.392A>G (p.Lys131Arg)

gnomAD frequency: 0.00006  dbSNP: rs397516805
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000654924 SCV001192858 likely benign RASopathy 2019-08-19 reviewed by expert panel curation The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Universite Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037646 SCV000061308 uncertain significance not specified 2011-06-12 criteria provided, single submitter clinical testing The Lys131Arg variant in PTPN11 has been reported in the literature in one Chine se individual with clinical features of Noonan syndrome (Chan 2006). This varian t was identified in that individual's mother; however clinical features for the mother were not provided. In addition, this variant has been detected by our lab oratory in one Asian proband who also has a pathogenic MEK1 variant. The Lys131 residue is highly conserved across mammals and lower species and computational a nalyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Lys131Arg variant may impa ct the normal function of PTPN11. Given this information, we are unable to make a conclusive determination as to whether this variant is responsible for the cli nical features observed in this individual.
GeneDx RCV000680297 SCV000514316 likely benign not provided 2020-06-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30896080, 24728327)
Ambry Genetics RCV000621552 SCV000736206 likely benign Cardiovascular phenotype 2021-04-14 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 RCV000654924 SCV000776830 likely benign RASopathy 2024-01-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037646 SCV001337714 likely benign not specified 2022-01-09 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.392A>G (p.Lys131Arg) results in a conservative amino acid change located in the SH2 domain 2 (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 282784 control chromosomes, predominantly at a frequency of 0.0007 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of 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 East Asian origin. The variant, c.392A>G, has been reported in the literature in Chinese individuals, who were affected with Noonan Syndrome and Related Conditions (Chan_2006, Yu_2019), however without providing supportive evidence for causality. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. In addition, the variant was also reported in healthy individuals of East Asian ancestry (Bodian_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813328 SCV002060824 uncertain significance Noonan syndrome and Noonan-related syndrome 2016-12-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496598 SCV002811182 likely benign Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2021-09-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000680297 SCV004562183 likely benign not provided 2023-09-22 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004534799 SCV004719100 likely benign PTPN11-related disorder 2022-01-25 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI RCV000037646 SCV000086117 not provided not specified 2013-09-19 no assertion provided reference population
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000678902 SCV000805102 uncertain significance Noonan syndrome 2017-03-08 no assertion criteria provided clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré RCV000678902 SCV001438509 likely benign Noonan syndrome no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.