rs121918459
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PP1_StrongPP2PP3PM1PS3PS4
This summary comes from the ClinGen Evidence Repository: The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) 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; PMID: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: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220146/MONDO:0018997/004
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
Publications
- LEOPARD syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
- Noonan syndrome with multiple lentiginesInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- metachondromatosisInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
- cardiofaciocutaneous syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | MANE Select | c.188A>G | p.Tyr63Cys | missense | Exon 3 of 16 | NP_002825.3 | ||
| PTPN11 | NM_001330437.2 | c.188A>G | p.Tyr63Cys | missense | Exon 3 of 16 | NP_001317366.1 | |||
| PTPN11 | NM_001374625.1 | c.185A>G | p.Tyr62Cys | missense | Exon 3 of 16 | NP_001361554.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | TSL:1 MANE Select | c.188A>G | p.Tyr63Cys | missense | Exon 3 of 16 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | TSL:5 | c.188A>G | p.Tyr63Cys | missense | Exon 3 of 15 | ENSP00000489597.1 | ||
| PTPN11 | ENST00000392597.5 | TSL:1 | c.188A>G | p.Tyr63Cys | missense | Exon 3 of 11 | ENSP00000376376.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 251010 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1460960Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726828 show subpopulations
Age Distribution
GnomAD4 genome 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:19Uncertain:1
The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
ACMG Criteria: PS1, PS3, PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
PS3, PS4, PM6, PP1, PP3, PP5
PS3, PM1, PM2, PP2, PP3, PP5
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22711529). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013333 /PMID: 11704759).The variant has been previously reported as de novo in a similarly affected individual (3billion dataset).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11704759, 12325025, 12634870, 16498234). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes); The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome. It is a 3-star pathogenic variant in ClinVar (reviewed by the ClinGen RASopathy Variant Curation Expert Panel), and is reported in the literature in individuals with Noonan syndrome (PMIDs: 11704759; 12325025; 12634870); The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870); Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER); Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from tyrosine to cysteine; This variant is heterozygous; This gene is known to be associated with autosomal dominant disease; Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250), and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187); Variants in this gene are known to have variable expressivity (PMID: 20301303); This variant has been shown to be maternally inherited by trio analysis.
not provided Pathogenic:15
PP1_strong, PP2, PP3, PM1, PS3_moderate
PTPN11: PP1:Strong, PM1, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting
The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys 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 (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. 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. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 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. PMID: 16358218
Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581)
Noonan syndrome Pathogenic:3
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.
The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) 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; PMID: 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: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024).
RASopathy Pathogenic:3
Variant classified using ACMG guidelines
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
PTPN11-related disorder Pathogenic:2
The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.
This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic.
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic
LEOPARD syndrome 1 Pathogenic:2
ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting
Noonan syndrome 3 Pathogenic:1
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.
Lymphoma;C3472624:B lymphoblastic leukemia lymphoma, no ICD-O subtype Pathogenic:1
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.
Metachondromatosis Pathogenic:1
Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Hereditary cancer-predisposing syndrome Pathogenic:1
PS4, PP1_strong, PM1, PS3_supporting, PP2, PP3 c.188A>G, located in exon 3 of the PTPN11 gene, is predicted to result in the substitution of tyrosine by cysteine at codon 63, p.(Tyr63Cys). This variant is found in 3/236472 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. It has been observed in multiple affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4, PP1_strong). This position affects a (potentially) clinically important functional domain (PM1). PTPN11 gene has a low rate of benign missense variants (PP2). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.984) suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997) (PP3). In vitro functional assays suggest that the p.Tyr63Cys variant could affect the protein's function (PMID:22711529) (PS3_supporting). This variant has been reported in the ClinVar database (46x pathogenic, 1x likely pathogenic), and in the LOVD database (21x likely pathogenic, 5x pathogenic), furthermore, it has been classified by the ClinGen RASopathy Variant Curation Expert Panel as pathogenic. Based on currently available information, the variant c.188A>G should be considered a pathogenic variant.
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at