rs397507548
Variant summary
Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.1517A>C(p.Gln506Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.
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 21 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.1517A>C | p.Gln506Pro | missense | Exon 13 of 16 | NP_002825.3 | ||
| PTPN11 | NM_001330437.2 | c.1529A>C | p.Gln510Pro | missense | Exon 13 of 16 | NP_001317366.1 | |||
| PTPN11 | NM_001374625.1 | c.1514A>C | p.Gln505Pro | missense | Exon 13 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.1517A>C | p.Gln506Pro | missense | Exon 13 of 16 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | TSL:5 | c.1529A>C | p.Gln510Pro | missense | Exon 13 of 15 | ENSP00000489597.1 | ||
| PTPN11 | ENST00000635652.1 | TSL:3 | c.530A>C | p.Gln177Pro | missense | Exon 5 of 5 | ENSP00000489541.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Published functional studies demonstrate p.(Q506P) affects the catalytic phosphatase domain (PTP) of the protein and interferes with its normal phosphatase activity (Qiu et al., 2014; Yu et. al, 2014); The majority of missense variants in this gene are considered pathogenic (HGMD); Located in the critical PTP functional domain and mutational hotspot region (Yu et al. 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15121796, 15928039, 16358218, 22528600, 24628801, 14961557, 30508783, 32164556, 14644997, 15987685, 26742426, 24803665, 18470943, 15723289, 20954246, 20301557, 30732632, 31219622, 33240318, 24935154)
PTPN11: PS2:Very Strong, PM1, PM2, PS4:Moderate, PP2, PS3:Supporting
RASopathy Pathogenic:3
The c.1517A>C (NM_002834.5(PTPN11):c.1517A>C (p.Gln506Pro) variant in PTPN11 is a missense variant predicted to cause substitution of glutamine by proline at amino acid 506 (p.Gln506Pro). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.9, 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 has been reported in 7 probands with clinical features of Noonan Syndrome with multiple lentigines (PS4; > 5.0 pts.; CeGaT (SCV001247473) & Ambry Genetics (SCV002708581) internal data, PMIDs: 14961557, 15928039, 20954246, 22528600). More evidence is available in the literature, but the score to apply PS4 at full strength has already been met. This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 4 individuals with Noonan Syndrome with Multiple Lentigines (PM6_strong, 3.5 points; CeGaT internal data (SCV001247473), PMIDs: 14961557, 15928039, 20954246). Enzyme-catalyzed hydrolysis of p-nitrophenyl phosphate analysis in E. Coli indicated reduced catalytic speed for the mutant. A study in HEK293 cells showed that the mutant performed dephosphorylation with greater efficiency and exhibited atypical behavior in ERK pathways. Another analysis in E. Coli showed increased dephosphorylation in the mutant. Each of these three assays indicate that the variant impacts protein function (PS3_moderate; PMIDs: 24935154, 26742426). 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, PS4, PM6_strong, PS3 (Specifications Version 2.3.0; 9/9/2025).
Variant summary: PTPN11 c.1517A>C (p.Gln506Pro) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes (gnomAD). c.1517A>C has been reported in the literature in individuals affected with Noonan Syndrome including de novo occurrences (Kratz_2005, Willig_2015, Li_2019, Athota_2020). These data indicate that the variant is likely to be associated with disease. Functional studies report this variant exhibits reduced catalytic activity (Yu_2014, Qiu_2014). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 506 of the PTPN11 protein (p.Gln506Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome or Noonan syndrome with multiple lentigines, some of whom also had a myeloproliferative disorder (PMID: 14961557, 15723289, 15928039, 18470943, 20954246, 22528600). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40563). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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: 15987685, 24935154, 26742426). For these reasons, this variant has been classified as Pathogenic.
Noonan syndrome 1 Pathogenic:2
The c.1517A>C is a known pathogenic variant that has been reported in multiple unrelated individuals with Noonan spectrum disorders [PMID: 14961557, 15121796,15928039, 15723289, 20954246, 22528600]. This variant is reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID:40563). The c.1517A>C variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1517A>C variant is located in exon 13 of this 16-exon gene and is predicted to replace an evolutionarily conserved glutamine amino acid with proline at position 506 in the protein-tyrosine phosphatase domain of the encoded protein [PMID: 24628801]. In silico predictions are in favor of damaging effect for p.(Gln506Pro) variant [(CADD v1.6 = 32, REVEL = 0.9)]. Published functional studies have shown reduced catalytic phosphatase activity of protein carrying the p.(Gln506Pro) variant [PMID: 15987685, 24628801, 24935154, 26742426]. Based on available evidence this de novo c.1517A>C p.(Gln506Pro) variant identified in PTPN11 is classified as Pathogenic.
The observed missense c.1517A>Cp.Gln506Pro variant in PTPN11 gene has been reported previously in heterozygous state in individuals affected with Noonan syndrome NS Piard et al., 2012. Experimental studies have shown that this missense change affects PTPN11 function Noda et al., 2016. This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The amino acid Gln at position 506 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gln506Pro in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic.
PTPN11-related disorder Pathogenic:2
This variant has been previously reported in several individuals with PTPN11-related disorders (PMID: 14961557, 15928039, 22528600, 30732632, 31219622, 32164556), and it was a de novo change in at least three patients (PMID: 30732632). In-vitro functional assessment of this alteration revealed that it affects the normal phosphatase activity of the protein (PMID: 15987685, 24935154, 24628801). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1529A>C (p.Gln510Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1529A>C (p.Gln510Pro) variant is classified as Pathogenic.
The PTPN11 c.1517A>C variant is predicted to result in the amino acid substitution p.Gln506Pro. This variant has been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (see for example - Conti et al. 2003. PubMed ID: 14961557; Athota et al. 2020. PubMed ID: 32164556) and in several of the individuals it was found to be de novo (see for example - Chen et al. 2019. PubMed ID: 30732632). Functional and structural studies found this variant inhibits catalytic activity (Keilhack et al. 2005. PubMed ID: 15987685; Qiu et al. 2014. PubMed ID: 24628801; Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Noonan syndrome with multiple lentigines Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory
Congenital long QT syndrome Pathogenic:1
The c.1517A>C missense variant in PTPN11 is absent from population databases like gnomAD, indicating rarity (PM2). It was not observed in other affected family members. In silico predictions (SIFT: 0.001) suggest a damaging effect (PP3), and the variant affects a conserved region of the protein (PM1). Based on these factors, the variant is classified as likely pathogenic (ACMG codes: PM1, PM2, PP3, PP5).
Noonan syndrome Pathogenic:1
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987685; 24935154; 26742426) - PS3.The c.1517A>C;p.(Gln506Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40563; PMID: 18470943; PMID: 14961557; PMID: 15723289; PMID: 15928039; PMID: 20954246; PMID: 22528600) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Y_phosphatase) - PM1. This variant is not present in population databases (rs397507548- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. 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.
Cardiovascular phenotype Pathogenic:1
The p.Q506P pathogenic mutation (also known as c.1517A>C), located in coding exon 13 of the PTPN11 gene, results from an A to C substitution at nucleotide position 1517. The glutamine at codon 506 is replaced by proline, an amino acid with similar properties. This mutation was first described as a de novo occurrence, paternity not confirmed, in a patient with a clinical diagnosis of Noonan syndrome with multiple lentigines (NSML, referred to as LEOPARD syndrome) including findings of mild hypertelorism, pulmonic stenosis, unilateral sensorineural hearing loss, and mild cognitive impairment (Conti E et al. Hum. Mutat., 2003 Jun;21:654). It has subsequently been reported in additional patients with Noonan syndrome or NSML (Derbent M et al. Am. J. Med. Genet. A, 2010 Nov;152A:2768-74; Piard J et al. Am. J. Med. Genet. A, 2012 Jun;158A:1406-10). Structural and functional studies indicate that this mutation results in a weakened auto-inhibited enzyme conformation leading to prolonged substrate turnover, producing a gain-of-function rasopathy phenotype through sustained activation of the RAS-ERK pathway (Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
LEOPARD syndrome 1 Other:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at