12-112450395-C-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.215C>G(p.Ala72Gly) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A72D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.215C>G | p.Ala72Gly | missense_variant | Exon 3 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.215C>G | p.Ala72Gly | missense_variant | Exon 3 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:8
ACMG codes: PS4M, PM2, PP3, PP5 -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - 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). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed in individuals with Noonan syndrome (PMID: 21784453). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
The variant is not observed in the gnomAD v2.1.1 dataset. 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. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013325 /PMID: 11704759). Different missense changes at the same codon (p.Ala72Asp, p.Ala72Pro, p.Ala72Ser, p.Ala72Thr, p.Ala72Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013324, VCV000040500, VCV000041443, VCV000177754, VCV000376511 /PMID: 11704759, 18759865, 30868567, 30896080). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided Pathogenic:6
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Published functional studies demonstrate increased activation of ERK1/2 (Sun et al., 2018); The majority of missense variants in this gene are considered pathogenic (HGMD); 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: 15956085, 12960218, 34241941, 34728626, 11992261, 15928039, 19020799, 11704759, 24803665, 30355600, 30541462, 30417923, 26918529, 29907801, 31219622, 31560489, 32164556, 9491886, 16053901, 29493581, 29568093, 31785789) -
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PS4, PM1, PM2, PM6_Strong, PP2, PP3 -
The PTPN11 c.215C>G; p.Ala72Gly variant (rs121918454) is reported in the literature in multiple individuals affected with Noonan syndrome, including several occurrences de novo (Ferreira 2005, Gabriel 2022, Lee 2011, Li 2019, Tartaglia 2002, Tartaglia 2006). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant occurs in the functionally important N-terminal SH2 domain involved in catalytic regulation, and computational analyses predict that this variant is deleterious (REVEL: 0.924). Multiple other missense variants at the same codon (p.Ala72Ser, p.Ala72Thr) have also been reported in individuals affected with Noonan syndrome and are considered disease-causing (Gabriel 2022, Tartaglia 2002, Tartaglia 2006). Based on available information, the p.Ala72Gly variant is considered to be pathogenic. References: Ferreira LV et al. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5156-60. PMID: 15956085. Gabriel H et al. Trio exome sequencing is highly relevant in prenatal diagnostics. Prenat Diagn. 2022 Jun;42(7):845-851. PMID: 34958143. Lee BH et al. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011 Dec;159(6):1029-35. PMID: 21784453. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. 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. 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. -
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Noonan syndrome Pathogenic:2
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The p.Ala72Gly variant in PTPN11 has been previously identified in >10 individua ls with clinical features of Noonan syndrome (Tartaglia 2001, Sarkozy 2003, Ferr eira 2005, Kratz 2005, Ko 2008, LMM data) and 1 individual with Noonan syndrome and myeloproliferative disorder (Kratz 2005). This variant was reported to have occurred de novo in at least four of these individuals (Ferreira 2005, LMM data) . It was absent from large population studies. This variant has also been report ed in ClinVar (Variation ID 13325). Several other variants involving this codon (p.Ala72Pro, p.Ala72Thr, p.Ala72Ser, p.Ala72Val) have been reported as pathogen ic. In summary, this variant meets criteria to be classified as pathogenic for N oonan in an autosomal dominant manner based upon case observations, de novo occu rrences, presence of other pathogenic variants at this codon, and absence from c ontrols. ACMG/AMP Criteria applied: PS4; PM5_Strong; PM6_Strong; PM2. -
Noonan syndrome 3 Pathogenic:1
Variant summary: The PTPN11 c.215C>G (p.Ala72Gly) variant involves the alteration of a highly conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The Ala72 codon is located within the N-SH domain and interacts directly with PTP domain residue Glu506. Although p.Ala72Gly has not been tested in functional studies, other alterations of this codon, p.Ala72Val and p.Ala72Ser, were shown to promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway (Tartaglia, 2006). The variant is absent from control datasets of ExAC and gnomAD (121394 chrs and 245816 chrs tested, respectively), however was reported in multiple affected individuals with clinically confirmed dx of NS and NSRD (Tartaglia, 2001; Tartaglia, 2006, Sarkozy, 2003 and Ezquieta, 2012) including several de novo events. The codon Ala72 appears to be a mutational hot-spot, as other alteration, such as p.A72P, p.A72V, p.A72S have been reported in patients with NS and NSRD. In addition, multiple reputable databases/clinical laboratories cite the variant as Pathogenic. Taking together, the variant of interest was classified as Pathogenic. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The p.A72G pathogenic mutation (also known as c.215C>G), located in coding exon 3 of the PTPN11 gene, results from a C to G substitution at nucleotide position 215. The alanine at codon 72 is replaced by glycine, an amino acid with similar properties. This mutation is located between the SH2 and PTP domains of PTPN11 and been detected in several individuals with clinically diagnosed Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ko JM et al. J. Hum. Genet., 2008 Dec;53:999-1006), one of which was a de novo occurrence; however, paternity was not confirmed (Ferreira LV et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5156-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
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RASopathy Pathogenic:1
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 72 of the PTPN11 protein (p.Ala72Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and hypertrophic cardiomyopathy and mitral valve anomaly (PMID: 11704759, 12960218, 15001945, 15956085, 19020799). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13325). 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%. This variant disrupts the p.Ala72 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 12161469, 14974085, 16399795, 17339163, 18678287, 26918529). 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