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

gnomAD frequency: 0.00006  dbSNP: rs397516805

Total submissions: 13

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