ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.329A>C (p.Glu110Ala) (rs397507519)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033485 SCV000057390 likely pathogenic not provided 2019-11-13 criteria provided, single submitter clinical testing Reported previously in a patient with Noonan syndrome, however further clinical details and information about parental testing was not provided (Zenker et al., 2004; Tartaglia et al., 2006); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18470943, 22681964, 24803665, 16358218, 16053901, 15001945, 24150203, 31827275)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002539 SCV001160502 likely pathogenic not specified 2019-04-16 criteria provided, single submitter clinical testing The PTPN11 c.329A>C; p.Glu110Ala variant (rs397507519) is reported in the literature in several individuals affected with Noonan syndrome or a related RASopathy (Tartaglia 2006, Zenker 2004). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by a single laboratory in ClinVar (Variation ID: 40508). The glutamate at codon 110 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant occurs in the linker between the N- and C-terminal SH2 domains, and it is predicted to influence the orientation or mobility of these domains (Tartaglia 2006). Additionally, another variant at this amino acid (p.Glu110Lys) has been reported in several individuals with Noonan syndrome or another RASopathy (Ezquieta 2012, Rodriguez 2014). Based on available information, the p.Glu110Ala variant is considered to be likely pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. Rodriguez FA et al. Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome. J Pediatr Endocrinol Metab. 2014 Mar;27(3-4):305-9. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 Mar;144(3):368-74.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001089572 SCV001244777 likely pathogenic Noonan syndrome 1 2018-06-26 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_002834.3(PTPN11):c.329A>C, has been identified in exon 3 of 16 of the PTPN11 gene. The variant is predicted to result in an amino acid change from glutamic acid to alanine at position 110 of the protein (NP_002825.3(PTPN11):p.(Glu110Ala)). The glutamic acid residue at this position hasvery high conservation (100 vertebrates, UCSC), and is located within the Linker region that connects the N-SH2 and C-SH2 functional domains. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in individuals with Noonan syndrome (ClinVar, Zenker et al., (2004)). A different variant in the same codon resulting in a change to lysine has also been reported to cause Noonan syndrome and the variant was shown to be de novo (ClinVar, Ezquieta et al., (2012)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Invitae RCV001221785 SCV001393847 pathogenic Rasopathy 2019-06-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 110 of the PTPN11 protein (p.Glu110Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Noonan syndrome (PMID: 15001945), and was also observed to be de novo in another individual with clinical features of RASopathy spectrum disorders (Invitae). ClinVar contains an entry for this variant (Variation ID: 40508). 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: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Glu110 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22465605, 24150203, 24451042, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001221785 SCV001572403 pathogenic Rasopathy 2021-04-05 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.329A>C (p.Glu110Ala) results in a non-conservative amino acid change located in the linker region that connects the N-SH2 and C-SH2 functional domains (Tartaglia_2006) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251352 control chromosomes (gnomAD and publication). c.329A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome or Pulmonary valve stenosis (Zenker_2004, Tartaglia_2006, Digilio_2012, Downie_2019). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue, E110K, was found in individuals affected with Noonan Syndrome (HGMD), suggesting that this variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

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