12-112473040-T-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_002834.5(PTPN11):c.853T>C(p.Phe285Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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 Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F285S) has been classified as Pathogenic.
Frequency
Consequence
NM_002834.5 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.853T>C | p.Phe285Leu | missense_variant, splice_region_variant | Exon 7 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.853T>C | p.Phe285Leu | missense_variant, splice_region_variant | Exon 7 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.96e-7 AC: 1AN: 1436904Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 716352
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6
- -
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 24183200, 28483241, 17339163, 17222357, 15689434, 34136918, 24803665, 26918529, 23771920, 22848035, 19120036, 15996221, 19303148, 11992261, 11704759, 17056636, 16523510, 12960218, 16124853, 18854871, 17020470, 16377799, 12717436, 18678287, 18470943, 27619028, 26297936, 26249544, 21533187, 21500339, 21396583, 19467855, 19206169, 9222968, 8530013, 1543375, 4025385, 1258892, 4386970, 30417923, 30050098, 29907801, 31219622, 31560489, 31324109, 32565546, 33300679, 34134972, 27521173, 29493581) -
The PTPN11 c.853T>C; p.Phe285Leu variant (rs397507531) is reported in the literature in individuals affected with Noonan or Noonan-like syndrome (Ferrero 2008, Jafarov 2005, Tartaglia 2002). This variant is reported as pathogenic five times in ClinVar (Variation ID: 40528) and is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant, c.855T>G, which results in the same amino acid change at codon 285, has also been reported in individuals affected with Noonan syndrome (Hung 2007). The phenylalanine at codon 285 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Additional variants resulting in different amino acid changes at this codon (Phe285Cys, Phe285Ile, Phe285Ser) have also been reported in individuals with Noonan syndrome (Aoki 2008, Ferrero 2008, Hung 2007), suggesting a critical role for this residue in protein function. Based on the above information, this variant is considered pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Ferrero G et al. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. 2008;51(6):566-72. Hung C et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. Jafarov T et al. Noonan-like syndrome mutations in PTPN11 in patients diagnosed with cherubism. Clin Genet. 2005 Aug;68(2):190-1. 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. -
PTPN11: PS1, PS2, PM2, PM5, PS4:Moderate, PP3 -
- -
- -
Noonan syndrome 1 Pathogenic:5
- -
PS1, PS4, PM1, PM2, PP3, PP5 - Same amino acid change as a known pathogenic variant. Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Noonan syndrome. (PMID:32164556). -
- -
- -
The variant is not observed in the gnomAD v2.1.1 dataset. 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. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040528) and different missense changes at the same codon (p.Phe285Cys, p.Phe285Ile, p.Phe285Ser, p.Phe285Tyr, p.Phe285Val / ClinVar ID: VCV000013335, VCV000040527, VCV000040533, VCV000181499, VCV000636408) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
LEOPARD syndrome 1 Pathogenic:2
- -
- -
Metachondromatosis Pathogenic:1
- -
PTPN11-related disorder Pathogenic:1
The PTPN11 c.853T>C variant is predicted to result in the amino acid substitution p.Phe285Leu. This variant has been reported in multiple individuals with Noonan Syndrome and in several cases it was determined to be de novo (see for examples Tartaglia et al. 2002. PubMed ID: 11992261; Nyström et al. 2009. PubMed ID: 19120036; van Trier et al. 2016. PubMed ID: 27521173). A different nucleotide substitution (c.855T>G) resulting in the same missense variant has been reported in multiple individuals with Noonan syndrome (Hung et al. 2007. PubMed ID: 17339163). Additionally, different missense variants affecting this amino acid (p.Phe285Ile, p.Phe285Val, p.Phe285Tyr, p.Phe285Ser, p.Phe285Cys) have been reported to be pathogenic (Ferrero et al. 2008. PubMed ID: 18678287; El Naofal et al. 2023. PubMed ID: 36703223; Yu et al. 2019. PubMed ID: 30896080; Tartaglia et al. 2002. PubMed ID: 11992261; Tartaglia et al. 2006. PubMed ID: 16358218). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40528). This variant is interpreted as pathogenic. -
Noonan syndrome Pathogenic:1
The p.Phe285Leu variant in PTPN11 has been associated with the clinical features of Noonan syndrome as well as Noonan-like/multiple giant-cell lesion syndrome ( Tartaglia 2002, Nystrom 2008, Jafarov 2005, Lee 2005, LMM unpublished data). Thi s variant has been observed to have occurred de novo in sporadic cases of Noonan syndrome. Furthermore, a different nucleotide substitution, c.855T>G, that resu lts in the same amino acid change has been identified in a sporadic case of Noon an syndrome (Hung 2007). Therefore, this variant meets our criteria to be classi fied as pathogenic. -
Noonan syndrome 3 Pathogenic:1
Variant summary: The PTPN11 c.853T>C (p.Phe285Leu) variant involves the alteration of a conserved nucleotide at the end of the exon 7. 3/4 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. There are no published functional studies for this variant. However, this variant is located in the PTP domain (InterPro), which is known to be important for protein function. This variant is absent in 118444 control chromosomes and is reported as a pathogenic variant found in several patients with NS or NS-related syndrome. It has also been reported as a de novo variant multiple instances. A different nucleotide substitution, c.855T>G, that results in the same amino acid change has been identified in a sporadic case of Noonan syndrome (Hung_JFMA_2007) and is classified as pathogenic by two labs in ClinVar. In addition, other substitutions (F285C, F285I and F285S) have been reported at this codon in association with Noonan syndrome (Tartaglia et al., 2006; Ferrero et al., 2008; Tartaglia et al., 2002). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Disease Variant/Pathogenic. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
- -
Cardiovascular phenotype Pathogenic:1
The c.853T>C (p.F285L) alteration is located in exon 7 (coding exon 7) of the PTPN11 gene. This alteration results from a T to C substitution at nucleotide position 853, causing the phenylalanine (F) at amino acid position 285 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been described in multiple individuals with a clinical diagnosis of Noonan syndrome (Tartaglia, 2002; Chinton, 2019) and in other patients with Noonan syndrome-like features (Jafarov, 2005; Nyström, 2009). Another nucleotide substitution within the same codon, c.855T>G, has also been observed to result in p.F285L, and has also been described in multiple individuals with a clinical diagnosis of Noonan syndrome (Hung, 2007; Athota, 2020). Furthermore, additional alterations affecting amino acid residue F285 (p.F285C, p.F285S, p.F285I) have been described in individuals with Noonan syndrome (Tartaglia, 2006; Ferrero, 2008; Essawi, 2013). This amino acid position is highly conserved in available vertebrate species. The p.F285L amino acid is located in the protein tyrosine phosphatase (PTP) functional domain of the SHP-2 protein, and is predicted to disrupt the interdomain interaction with the N-SH2 domain, which normally stabilizes the inactive conformation of the protein (Tartaglia, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
RASopathy Pathogenic:1
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the PTPN11 protein (p.Phe285Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan or Noonan-like syndrome (PMID: 11992261, 15689434, 15996221, 23771920). ClinVar contains an entry for this variant (Variation ID: 40528). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 function. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17339163, 18470943, 18678287). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at