ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.188A>G (p.Tyr63Cys) (rs121918459)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000157000 SCV000616372 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.188A>G (p.Tyr63Cys) variant in PTPN11 has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; 16498234, 12634870, 12325025, 11704759). In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). 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; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP1_Strong, PS4, PS3, PM1, PP2, PP3.
GeneDx RCV000077857 SCV000057373 pathogenic not provided 2018-12-06 criteria provided, single submitter clinical testing The Y63C variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2001; Maheshwari et al., 2002; Musante et al., 2003), and has been observed to occur de novo in patients tested at GeneDx. The Y63C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y63C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. The autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state, is perturbed by Y63C as a result of structural rearrangement of the N-SH2 domain (Martinelli et al., 2012). Furthermore, missense variants in nearby residues (T59A, G60C/S/A, D61H/N/A/G, Y62D/N/C) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret Y63C as a pathogenic variant
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077857 SCV000058290 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000157000 SCV000061294 pathogenic Noonan syndrome 2017-04-20 criteria provided, single submitter clinical testing The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong.
Blueprint Genetics RCV000157000 SCV000207167 pathogenic Noonan syndrome 2015-01-07 criteria provided, single submitter clinical testing
Invitae RCV000033468 SCV000253879 pathogenic Rasopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 63 of the PTPN11 protein (p.Tyr63Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs121918459, ExAC 0.01%). This variant has been observed in many individuals affected with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 16498234, 21407260) and reportedly segregates with disease in multiple families (PMID: 12325025, 12960218, 16498234). ClinVar contains an entry for this variant (Variation ID: 13333). Experimental studies have shown that this missense change affects the structural conformation of the PTPN11 protein, resulting in an aberrant increase in protein activity (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000077857 SCV000265840 pathogenic not provided 2015-09-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515408 SCV000611303 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000077857 SCV000614839 pathogenic not provided 2017-06-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588678 SCV000698066 pathogenic Noonan syndrome 3 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.
Undiagnosed Diseases Network,NIH RCV000014261 SCV000746635 pathogenic Noonan syndrome 1 2017-03-28 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000014261 SCV000782248 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722014 SCV000853187 pathogenic Lymphoma; B lymphoblastic leukemia lymphoma, no ICD-O subtype 2017-04-26 criteria provided, single submitter clinical testing This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000077857 SCV000884430 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing The p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Okamoto 2014). This variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons have also been identified in Noonan patients (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphoERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. References: Hashida N et al. (2013) MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 13:70. Hof P et al. (1998) Crystal structure of the tyrosine phosphatase SHP-2. Cell. 92(4): 441-450.Jongmans M et al. (2011) Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 19(8):870-4. Jongmans M et al. (2011) Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 19(8):870-4. Martinelli S et al. (2012) Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 287(32):27066-77. Okamoto N et al. (2015) Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 88(3):288-92. Tartaglia M et al. (2001) Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 29(4):465-8. Tartaglia M et al. (2002) PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 70(6): 1555-1563. Tartaglia M et al. (2006) Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 78(2): 279-290.
Institute for Genomic Statistics and Bioinformatics,University Hospital Bonn RCV000014261 SCV000999303 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
OMIM RCV000014261 SCV000034509 pathogenic Noonan syndrome 1 2007-06-01 no assertion criteria provided literature only
Baylor Genetics RCV000033468 SCV000196657 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157000 SCV000206724 pathogenic Noonan syndrome 2013-12-23 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000077857 SCV000207652 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Baylor Genetics RCV000014261 SCV000854621 pathogenic Noonan syndrome 1 2018-11-18 no assertion criteria provided clinical testing

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