ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.179G>T (p.Gly60Val)

dbSNP: rs397507509
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000049228 SCV000077242 pathogenic not provided 2021-09-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 27959697, 32499245, 27923552, 31130284, 18701506, 16358218, 15928039, 27460089, 30050098, 29296745, 32934818, 29493581, 16053901, 9491886, 11992261)
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000414941 SCV001370261 pathogenic Noonan syndrome 1 2019-05-27 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1,PS2,PM1,PP3.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813372 SCV002060795 pathogenic Noonan syndrome and Noonan-related syndrome 2019-09-01 criteria provided, single submitter clinical testing
DASA RCV000414941 SCV002061169 pathogenic Noonan syndrome 1 2022-01-05 criteria provided, single submitter clinical testing The c.179G>T;p.(Gly60Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: ClinVar ID: 55797; PMID: 29907801; 18470943; 18701506) -.PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 30375388) - PMID: 30375388 The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2 domain) - PM1. This variant is not present in population databases (rs397507509 , gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID:40493; 987743; 40490; 372590; 41442) - PM5. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Institute of Human Genetics, University Hospital Muenster RCV002287357 SCV002577797 pathogenic See cases 2019-02-27 criteria provided, single submitter clinical testing ACMG categories: PS2,PM1,PM2,PP3,PP5
Labcorp Genetics (formerly Invitae), Labcorp RCV002513672 SCV003442010 likely pathogenic RASopathy 2022-03-12 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 55797). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 27959697). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the PTPN11 protein (p.Gly60Val). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly60 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 16643459, 17020470, 24039098, 26817465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 30375388). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003224860 SCV003920940 pathogenic Noonan syndrome 1; LEOPARD syndrome 1 2023-01-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000049228 SCV004562767 pathogenic not provided 2023-07-26 criteria provided, single submitter clinical testing The PTPN11 c.179G>T; p.Gly60Val variant (rs397507509) is reported in the literature in multiple individuals affected with Noonan syndrome (Leach 2019, Monies 2006, Posey 2017). This variant is also reported in ClinVar (Variation ID: 55797) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Ala, Cys, Ser) have been reported in individuals with Noonan syndrome and are considered pathogenic (Bertelloni 2013, Limal 2006). Computational analyses predict that this variant is deleterious (REVEL: 0.931). Based on available information, this variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. PMID: 23624134. Leach NT et al. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019 Feb;21(2):417-425. PMID: 29907801. Limal JM et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006 Jan;91(1):300-6. PMID: 16263833. Monies D et al. Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Am J Hum Genet. 2019 Jun 6;104(6):1182-1201. PMID: 31130284. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000414941 SCV005441990 pathogenic Noonan syndrome 1 2024-12-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000414941 SCV000328729 likely pathogenic Noonan syndrome 1 2014-04-09 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in PTPN11 (NM_002834.3, c.179G>T) and SHH (NM_000193.2, c.1284delC) in one individual with reported features of global developmental delay, hearing loss, hypotonia, hypertonia/spasticity, possible seizures, dysmorphic features (low frontal hairline, frontal bossing, deep set eye, downslanting palpebral fissures, broad based nose, upturned nasal tip), short 5th fingers, macrocephaly, structural brain abnormalities (agenesis of corpus callosum, large post interhemispheric cyst), possible cortical vision impairment, and an atrial septal defect.

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