ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.236A>G (p.Gln79Arg)

dbSNP: rs121918466
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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157680 SCV000057385 pathogenic not provided 2022-05-03 criteria provided, single submitter clinical testing In vitro expression of PTPN11-Q79R in cardiac cell cushions from chick embryos resulted in increased phosphatase activity and significantly increased outgrowth of cushion cells compared to wild-type protein expression (Krenz et al., 2005); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in the N-SH2 domain (Gelb 2018); This variant is associated with the following publications: (PMID: 22848035, 19017799, 17641779, 11704759, 24803665, 17020470, 16987887, 26855057, 11992261, 29396779, 12529711, 16166557, 19251646, 26607044, 22681964, 27521173, 27348588, 26817465, 12634870, 29084544, 29766225, 30417923, 30050098, 29907801, 31219622, 31560489, 32164556, 33318624, 34008892, 34006472, 35440950, 35178568, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037641 SCV000061303 pathogenic Noonan syndrome 2015-07-16 criteria provided, single submitter clinical testing The p.Gln79Arg variant in PTPN11 has been reported in >30 individuals with clini cal features of Noonan syndrome and segregated with disease in >10 affected rela tives (Tartaglia 2001, Tartaglia 2002, Schollen 2003, Musante 2003, Yoshida 2004 , Zenker 2004, Chan 2006, Bertola 2006, LMM unpublished data). This variant has also occurred de novo in multiple affected individuals (LMM unpublished data). I t has not been identified in large population studies. In-vivo animal models and in-vitro studies provide evidence that the p.Gln79Arg variant impacts protein f unction (Krenz 2005, Nakamura 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant man ner based upon segregation studies, de novo occurrences in affected individuals, extremely low frequency in the general population, and functional evidence.
Invitae RCV000033480 SCV000253880 pathogenic RASopathy 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 79 of the PTPN11 protein (p.Gln79Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11704759, 11992261, 12529711, 12634870, 17020470, 22848035). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13340). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16166557, 17641779, 19017799). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000157680 SCV000265842 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000515381 SCV000611306 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590740 SCV000698073 pathogenic Noonan syndrome 3 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.236A>G (p.Gln79Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. It is located at N-SH2 domain of the protein (InterPro) which is a known functionally important domain in PTPN11 protein. This variant is absent in 121794 control chromosomes. This variant has been widely reported as a pathogenic variant in literature found in many Noonan Syndrome (NS) and/or Noonan Syndrome and Related Conditions (NSRD), including reports of de novo occurrences and co-segregation with disease (Tartaglia_2001, Schollen_2003, Niihori_2005, Ezquieta_2012, Karback_2012). In vitro studies show that this mutant results in significantly elevated phosphatase activity and endocardial cushion growth (Krenz_2005). Furthermore, in vivo mice expression model showed that this mutant leads to embryonic lethality and the embryonic hearts showed altered cardiomyocyte cell cycling ventricular noncompaction, and ventricular septal defects. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2 (Nakamura_2007). Another variant at the same residue, p.Q79K, has also been reported in NSRD patients (PMIDs: 12960218, 22848035, 16358218) and is classified as likely pathogenic by a clinical lab in ClinVar. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000014268 SCV000782249 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157680 SCV000928050 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000014268 SCV000999314 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000014268 SCV001451638 pathogenic Noonan syndrome 1 2019-02-26 criteria provided, single submitter clinical testing Across a selection of the available literature, the PTPN11 c.236A>G (p.Gln79Arg) missense variant has been identified in a heterozygous state in at least 13 individuals from four unrelated families affected with Noonan syndrome (Schollen et al. 2003; Niihori et al. 2005; Atik et al. 2016). Schollen et al. (2003) reported a large four generation Belgian family with ten affected members, in whom the p.Gln79Arg variant segregated with Noonan syndrome. The p.Gln79Arg variant was absent from 100 healthy controls and is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is rare. The Gln79 residue in present in the N-SH2 domain, which functions as an intra-molecular switch to control the protein's catalytic activity (Schollen et al. 2003; Nakamura et al. 2007). Functional studies in HEK293 cells, rat cardiomyocytes and chick valve explants found that the p.Gln79Arg is a gain-of-function variant resulting in increased MAPK 1/2 signaling and thereby increased growth, which can be reversed by use of MAPK 1/2 inhibitors (Niihori et al. 2005; Krenz et al. 2005). In addition, transgenic mice expressing the p.Gln79Arg variant protein in cardiomyocytes during gestation, showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects (Nakamura et al. 2007). Based on the collective evidence and application of the ACMG criteria, the p.Gln79Arg variant is classified as pathogenic for Noonan syndrome.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000014268 SCV001976968 pathogenic Noonan syndrome 1 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PM5, PP3, PP4, PP5
Revvity Omics, Revvity RCV000157680 SCV002019549 pathogenic not provided 2019-05-07 criteria provided, single submitter clinical testing
3billion RCV000014268 SCV002058830 pathogenic Noonan syndrome 1 2022-01-03 criteria provided, single submitter clinical testing he variant has been previously reported as de novo in a similarly affected individual (PMID: 22848035, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013340, PS1_S). The variant was co-segregated with Noonan syndrome 1 in multiple affected family members (PMID: 11704759, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.973, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044605, PM5_M). TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813202 SCV002060936 pathogenic Noonan syndrome and Noonan-related syndrome 2021-05-27 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000014268 SCV002557728 pathogenic Noonan syndrome 1 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines (MIM#151100) are associated with loss of function while Noonan syndrome 1 (MIM#163950) is associated with gain of function (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity and associated with Noonan syndrome (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Gln79His): 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher) within the N terminal SH2 domain (Decipher, NCBI). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Gln79Lys) and p.(Gln79Pro) variants have been reported in individuals with Noonan syndrome (PMID: 12960218; ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least ten individuals diagnosed with Noonan syndrome and has been classified as pathogenic by multiple clinical diagnostic laboratories (PMIDs: 16358218, 32164556; ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics RCV002453257 SCV002735849 pathogenic Cardiovascular phenotype 2023-07-03 criteria provided, single submitter clinical testing The c.236A>G (p.Q79R) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from an A to G substitution at nucleotide position 236, causing the glutamine (Q) at amino acid position 79 to be replaced by an arginine (R). This clinical significance of this variant is unclear for metachondromatosis; however, it would be expected to be causative of PTPN11-related RASopathy based on mechanism of disease. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation segregated in 3 individuals with Noonan syndrome and was absent from 2 unaffected individuals in one family (Tartaglia, 2001); it was also identified in a sporadic case (Tartaglia, 2001) and de novo in another affected individual (Karbach, 2012). This amino acid position is highly conserved in available vertebrate species. Activity studies in rat neonatal cardiomyocytes showed this alteration results in a gain-of-function of the protein, with a 4.5 times higher activity compared to wild type (Krenz, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam RCV000014268 SCV003934956 pathogenic Noonan syndrome 1 2022-06-22 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000157680 SCV004026135 pathogenic not provided 2022-08-17 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV004532344 SCV004046235 pathogenic PTPN11-related disorder criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with Noonan syndrome (PMID: 11704759, 11992261, 12529711, 12634870, 17020470, 22848035). This variant is located in a mutational hotspot for pathogenic variants associated with Noonan syndrome. Pathogenic missense variants at the same amino acid residue (p.Gln79Pro) and nearby amnio acid residues (p.Glu76Asp, p.Glu76Gln, p.Glu76Gly, p.Glu76Val) have been reported in association with Noonan syndrome (PMID: 12960218, 24803665, 3279447, 20308328). Functional studies showed that the c.236A>G (p.Gln79Arg) variant is a gain-of-function variant that induces an increase of phosphatase activity and endocardial cushion growth (PMID: 16166557, 15834506). Animal studies in mice showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects when the c.236A>G (p.Gln79Arg) variant is present (PMID: 17641779). The c.236A>G (p.Gln79Arg) variant is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.236A>G (p.Gln79Arg) variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000157680 SCV004226877 pathogenic not provided 2022-03-14 criteria provided, single submitter clinical testing PP2, PP3, PM1, PM2_supporting, PS2, PS3, PS4
PreventionGenetics, part of Exact Sciences RCV004532344 SCV004741607 pathogenic PTPN11-related disorder 2024-02-13 criteria provided, single submitter clinical testing The PTPN11 c.236A>G variant is predicted to result in the amino acid substitution p.Gln79Arg. This variant has been identified in many individuals with Noonan syndrome (Tartaglia et al. 2001. PubMed ID: 11704759; Tartaglia et al. 2006. PubMed ID: 16358218; Karbach et al. 2012. PubMed ID: 22848035; van Trier et al. 2016. PubMed ID: 27521173; Xu et al. 2017. PubMed ID: 29084544; Athota et al. 2020. PubMed ID: 32164556). In one family it was found to segregate in 3 affected individuals (Tartaglia et al. 2001. PubMed ID: 11704759) and has been noted as a de novo event in at least two cases (Karbach et al. 2012. PubMed ID: 22848035; Fan et al. 2021. PubMed ID: 34006472). This variant has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13340/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
New York Genome Center RCV000014268 SCV005044112 pathogenic Noonan syndrome 1 2021-08-20 criteria provided, single submitter clinical testing The de novo c.236A>G (p.Gln79Arg) variant identified in the PTPN11 gene substitutes a well conserved Glutamine for Arginine at amino acid 79/594 (exon 3/16). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.933) and Damaging (SIFT; score:0.003) to the function of the canonical transcript. This variant is reported in ClinVar as Pathogenic/Likely Pathogenic (VarID:13340), and has been reported in many individuals in the literature with Noonan syndrome [PMID:12529711, 17020470, 26817465, 32164556, others] including a large multigeneration family with which it segregated with Noonan syndrome [PMID:12529711]. Functional studies suggest that the p.Gln79Arg variant increases ERK1/2 signaling [PMID:16166557]. The p.Gln79 residue is within the N-terminal SH2 domain, which is a hot spot for pathogenic PTPN11 variation [PMID:32164556]. Given its presence de novo in a mutational hotspot, absence in population databases, presence in many affected individuals in the literature, and functional studies suggesting increased MAPK signaling, the c.236A>G (p.Gln79Arg) variant identified in the PTPN11 gene is reported as Pathogenic.
OMIM RCV000014268 SCV000034517 pathogenic Noonan syndrome 1 2003-01-01 no assertion criteria provided literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037641 SCV000206693 pathogenic Noonan syndrome 2014-05-02 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000157680 SCV000207654 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000037641 SCV000805100 pathogenic Noonan syndrome 2016-07-06 no assertion criteria provided clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000014268 SCV001482317 pathogenic Noonan syndrome 1 2019-05-31 no assertion criteria provided research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000014268 SCV004041710 pathogenic Noonan syndrome 1 2023-10-09 no assertion criteria provided clinical testing

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