ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.392A>G (p.Lys131Arg) (rs397516805)

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Total submissions: 9
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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, Partners HealthCare 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 uncertain significance Cardiovascular phenotype 2018-05-31 criteria provided, single submitter clinical testing The p.K131R variant (also known as c.392A>G), located in coding exon 4 of the PTPN11 gene, results from an A to G substitution at nucleotide position 392. The lysine at codon 131 is replaced by arginine, an amino acid with highly similar properties. This variant was detected in one individual reported to have Noonan syndrome, though details were limited (Chan et al. HK J Peadr. 2006; 11(4):290-296). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV000654924 SCV000776830 uncertain significance Rasopathy 2020-09-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 131 of the PTPN11 protein (p.Lys131Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs397516805, ExAC 0.05%). This variant has been observed in individual(s) with Noonan syndrome (PMID: 30896080). ClinVar contains an entry for this variant (Variation ID: 44607). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037646 SCV001337714 likely benign not specified 2020-01-27 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. Four 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 (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
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

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