12-112473023-A-G
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.836A>G(p.Tyr279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y279S) has been classified as Pathogenic.
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 19 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.836A>G | p.Tyr279Cys | missense | Exon 7 of 16 | NP_002825.3 | ||
| PTPN11 | NM_001330437.2 | c.836A>G | p.Tyr279Cys | missense | Exon 7 of 16 | NP_001317366.1 | |||
| PTPN11 | NM_001374625.1 | c.833A>G | p.Tyr278Cys | missense | Exon 7 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.836A>G | p.Tyr279Cys | missense | Exon 7 of 16 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | TSL:5 | c.836A>G | p.Tyr279Cys | missense | Exon 7 of 15 | ENSP00000489597.1 | ||
| PTPN11 | ENST00000392597.5 | TSL:1 | c.836A>G | p.Tyr279Cys | missense | Exon 7 of 11 | ENSP00000376376.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1454492Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 723992 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
LEOPARD syndrome 1 Pathogenic:9Other:1
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 1 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by many clinical laboratories (ClinVar); This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from Tyr to Cys; This variant is heterozygous; This gene is associated with autosomal dominant disease; Variant is located in the annotated protein-tyrosine phosphatase domain (DECIPER); 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 (MIM#151100) 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; ClinGen expert panel).
This de novo mutation identified in the PTPN11 gene is one of the well-described mutations causing the LEOPARD syndrome.
The missense c.836A>G p.Tyr279Cys variant in the PTPN11 gene which is located in a mutational hot spot has been reported previously in a heterozygous state in individuals affected with LEOPARD syndrome Alfurayh et al., 2020. Published functional studies demonstrate weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation Yu et al., 2014; Kontaridis et al., 2006. A different amino acid change affecting codon 279 p.Tyr279Ser is reported as a known pathogenic variant. The amino acid Tyr at position 279 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic Multiple submitters. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Tyr279Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP2,PP3.
not provided Pathogenic:8
PTPN11: PS1, PM1, PM2, PP2, PP3
Published functional studies demonstrate weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation (Yu et al., 2014; Kontaridis et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15121796, 23312806, 26337637, 12161596, 15520399, 16358218, 20308328, 16172598, 16679933, 24820750, 24628801, 16377799, 16638574, 18372317, 18849586, 24037001, 11992261, 24034393, 24775816, 14991917, 24803665, 22822385, 25917897, 26377839, 19768645, 19725129, 28483241, 20493809, 21339643, 23457302, 23673659, 12058348, 19520282, 30732632, 30692697, 30417923, 26918529, 30050098, 31446693, 29907801, 31560489, 31722741, 32164556, 24935154, 24401936, 32866449, 33318624, 31589614, 33258288, 28252636, 9491886, 16053901, 29493581, 33855281)
This variant has been identified in multiple unrelated individuals with NSML. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16358218, 16638574, 16377799, 18372317)
Noonan syndrome 1 Pathogenic:4
RASopathy Pathogenic:4
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the PTPN11 protein (p.Tyr279Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome with multiple lentigines (NSML, also known as LEOPARD syndrome) (PMID: 15520399, 17020470, 22681964, 22822385, 24401936, 24820750, 25917897). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13328). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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: 16377799, 16638574, 18372317, 21339643, 23673659). For these reasons, this variant has been classified as Pathogenic.
The c.836A>G (NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys))variant in PTPN11 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 279 (p.Tyr279Cys). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.973, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to PTPN11 function (PP3). 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. The Z-score for missense variants in PTPN11 in gnomAD v4.1.0 is 4.95 (PP2; PMID: 29493581). This variant resides in a region (amino acids 278-281) of PTPN11 that is defined as a mutational hotspot and/or critical functional domain by the ClinGen RASopathy VCEP (PM1; PMID 29493581). This variant has been observed in 10 probands with clinical features of Noonan Syndrome with multiple lentigines (PS4, 7.0 pts.; PMIDs: 14634749, 15520399, 24401936, 24775816, 28483241). The variant was identified as a de novo occurrence with unconfirmed parental relationships in the father of an affected family (PM6, 1.0 pts.; PMID: 24401936). The variant segregated with disease in his 4 affected children (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_supporting, PP3, PP2, PM1, PS4, PM6, PP1 (Specifications Version 2.3.0; 9/9/2025).
Variant classified using ACMG guidelines
PTPN11-related disorder Pathogenic:2
The PTPN11 c.836A>G variant is predicted to result in the amino acid substitution p.Tyr279Cys. This variant has been well documented in multiple unrelated individuals to be causative for both Noonan and Leopard Syndromes (see for example - Legius et al. 2002. PubMed ID: 12161596; Tartaglia et al. 2002. PubMed ID: 11992261; Sarkozy et al. 2004. PubMed ID: 15121796; Tartaglia and Gelb. 2005. PubMed ID: 16124853). Functional studies demonstrate increased p-MEK/ERK levels, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Kontaridis et al. 2006. PubMed ID: 16377799; Hanna et al. 2006. PubMed ID: 16638574; Martinelli et al. 2008. PubMed ID: 18372317; Schramm et al. 2013. PubMed ID: 23673659; Yu et al. 2014. PubMed ID: 24935154). Additionally, a knockin mouse model of this variant demonstrates features consistent with Noonan syndrome (Marin et al. 2011. PubMed ID: 21339643). 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.
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 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 (PMID: 29493581). Missense variant. Missense changes are a common disease-causing mechanism.in silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (> 0.75, sensitivity 0.96 and precision 0.92)].The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013328 / PMID: 11992261 / 3billion dataset). A different missense change at the same codon (p.Tyr279Ser) has been reported to be associated with PTPN11-related disorder (ClinVar ID: VCV000065666 / PMID: 15121796).Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Noonan syndrome with multiple lentigines Pathogenic:1
Variant summary: PTPN11 c.836A>G (p.Tyr279Cys) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain 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 245584 control chromosomes (gnomAD). c.836A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (Keren_2004, Harakmi_2016). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies have indicated the variant abolishes enzymatic activity of PTPN11 and increases AKT, the variant's mechanism causes a gain of function (Yu_2014). The variant has been established to be a common disease variant by multiple publications. In addition, nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
not specified Pathogenic:1
The PTPN11 c.836A>G; p.Tyr279Cys variant (rs121918456) is reported in the literature in numerous individuals affected with Noonan syndrome and LEOPARD syndrome, also known as Noonan syndrome with multiple lentigines (Begic 2014, Digilio 2004, Legius 2002, Quaio 2013, Sarkozy 2004, Tartaglia 2002, Wang 2014). This is a recurrent variant reported to cosegregate with disease in families (Begic 2014, Legius 2002) and also observed de novo (Begic 2014, Digilio 2004, Wang 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13328), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 279 is highly conserved and interacts with an active site loop required for catalysis (Kontaridis 2006, Qiu 2014), and biochemical analyses demonstrate strongly reduced phosphatase activity of the p.Tyr279Cys variant (Hanna 2006, Qiu 2014). In both cultured cells and mice, the p.Tyr279Cys variant exhibits a dominant negative effect on Erk/MAPK signaling (Kontaridis 2006, Marin 2011), and the mouse model of PTPN11 p.Tyr279Cys recapitulates physiological symptoms of human LEOPARD syndrome, including skeletal abnormalities and hypertrophic cardiomyopathy (Marin 2011). Additionally, another variant at this codon (p.Tyr279Ser) has been reported in an individual with symptoms of LEOPARD syndrome (Sarkozy 2004), reiterating its functional importance. Based on available information, the p.Tyr279Cys variant is considered to be pathogenic. References: Begic F et al. Leopard syndrome: a report of five cases from one family in two generations. Eur J Pediatr. 2014 Jun;173(6):819-22. Digilio MC et al. Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. Birth Defects Res A Clin Mol Teratol. 2004 Feb;70(2):95-8. Hanna N et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006 May 1;580(10):2477-82. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. Legius E et al. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002 Aug;39(8):571-4. Marin TM et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011 Mar;121(3):1026-43. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 Mar 14;14:10. Quaio CR et al. Tegumentary manifestations of Noonan and Noonan-related syndromes. Clinics (Sao Paulo). 2013;68(8):1079-83. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. 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. Wang Y et al. Leopard syndrome caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene in a sporadic case of Chinese Han. Int J Cardiol. 2014 Jul 1;174(3):e101-4.
CBL-related disorder Pathogenic:1
The variant was detected in a neonate with congenital intrauterine revealed myocardial hypertrophy. The main clinical sign was myocardial hypertrophy and cardiac output deficit due to reduced LV cavity. No morphological signs of Noonan syndrome were observed. The variant was detected in combination with CBL NM_005188: exon11: c.G1754T :p.R585L variant in RAS-pathway (PMID 25731833).
Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines Pathogenic:1
The p.Tyr279Cys variant in PTPN11 has previously been reported in several indivi duals with clinical features of Noonan or LEOPARD syndrome, segregated with dis ease in multiple families, and occured as a de novo variant in sporadic cases (F roster 2003, Tartaglia 2006, Martinelli 2008, Tang 2009, Digilio 2002, Kalev 200 9, Legius 2002, Legius 2002, Oishi 2009). It was absent from large population st udies. In summary, this variant meets our criteria to be classified as pathogeni c for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner (http ://www.partners.org/personalizedmedicine/LMM).
Cardiovascular phenotype Pathogenic:1
The p.Y279C pathogenic mutation (also known as c.836A>G), located in coding exon 7 of the PTPN11 gene, results from an A to G substitution at nucleotide position 836. The tyrosine at codon 279 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple patients and families with a clinical diagnosis of Noonan syndrome or related disorder, most of whom had skin findings including multiple lentigines and/or cafe-au-lait spots, and several patients had hypertrophic cardiomyopathy or other cardiac findings (Tartaglia M, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Keren B, J. Med. Genet. 2004 Nov; 41(11):e117; Carcavilla A, Rev Esp Cardiol (Engl Ed) 2013 May; 66(5):350-6; Conboy E et al. J Med Genet. 2016;53(2):123-6). One study reported this mutation had occurred de novo in the index case, and co-segregated with disease in four affected offspring (Begi F, Eur. J. Pediatr. 2014 Jun; 173(6):819-22). The p.Y279C mutation is one of the most common mutations reported in Noonan syndrome and related disorders, it is in the protein tyrosine phosphatase (PTP) functional domain, and another pathogenic variant at the same codon, p.Y279S, has been reported in affected individuals (Tartaglia M, Eur J Med Genet. 2005 Apr; 48(2):81-96). In addition, a functional study of fibroblasts from individuals heterozygotes for this mutation, and HEK293 cells transfected with this mutation, showed significantly stronger EGF-induced phosphorylation of downstream targets when compared to normal controls (Edouard T, Mol. Cell. Biol. 2010 May; 30(10):2498-507). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
PTPN11 NM_002834.4 exon 7 p.Tyr279Cys (c.836A>G): This variant is a well established and commonly reported pathogenic variant in the literature, identified in several individuals with Noonan syndrome/LEOPARD syndrome, including a GeneReviews entry. This variant has been published as segregating with disease in multiple affected family members, and as a de novo occurence (Legius 2002 PMID:12161596, Tartaglia 2002 PMID:11992261, Kalev 2010 PMID:19768645, Begic 2014 PMID:24401936, Gelb 2015 PMID:20301557). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13328). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies (including a drosophila model) have shown a deleterious effect of this variant (Kontaridis 2006 PMID: 16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586). In summary, this variant is classified as pathogenic.
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at