12-112450416-A-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.236A>G(p.Gln79Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Q79P) 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.236A>G | p.Gln79Arg | missense_variant | Exon 3 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.236A>G | p.Gln79Arg | missense_variant | Exon 3 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461582Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727120
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:12
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The de novo c.236A>G (p.Gln79Arg) variant identified in the PTPN11 gene substitutes a well conserved Glutamine for Arginine at amino acid 79/594 (exon 3/16). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.933) and Damaging (SIFT; score:0.003) to the function of the canonical transcript. This variant is reported in ClinVar as Pathogenic/Likely Pathogenic (VarID:13340), and has been reported in many individuals in the literature with Noonan syndrome [PMID:12529711, 17020470, 26817465, 32164556, others] including a large multigeneration family with which it segregated with Noonan syndrome [PMID:12529711]. Functional studies suggest that the p.Gln79Arg variant increases ERK1/2 signaling [PMID:16166557]. The p.Gln79 residue is within the N-terminal SH2 domain, which is a hot spot for pathogenic PTPN11 variation [PMID:32164556]. Given its presence de novo in a mutational hotspot, absence in population databases, presence in many affected individuals in the literature, and functional studies suggesting increased MAPK signaling, the c.236A>G (p.Gln79Arg) variant identified in the PTPN11 gene is reported as Pathogenic. -
PM1, PM2, PM5, PP3, PP4, PP5 -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31836589). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000694038 /PMID: 24938718 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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Across a selection of the available literature, the PTPN11 c.236A>G (p.Gln79Arg) missense variant has been identified in a heterozygous state in at least 13 individuals from four unrelated families affected with Noonan syndrome (Schollen et al. 2003; Niihori et al. 2005; Atik et al. 2016). Schollen et al. (2003) reported a large four generation Belgian family with ten affected members, in whom the p.Gln79Arg variant segregated with Noonan syndrome. The p.Gln79Arg variant was absent from 100 healthy controls and is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is rare. The Gln79 residue in present in the N-SH2 domain, which functions as an intra-molecular switch to control the protein's catalytic activity (Schollen et al. 2003; Nakamura et al. 2007). Functional studies in HEK293 cells, rat cardiomyocytes and chick valve explants found that the p.Gln79Arg is a gain-of-function variant resulting in increased MAPK 1/2 signaling and thereby increased growth, which can be reversed by use of MAPK 1/2 inhibitors (Niihori et al. 2005; Krenz et al. 2005). In addition, transgenic mice expressing the p.Gln79Arg variant protein in cardiomyocytes during gestation, showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects (Nakamura et al. 2007). Based on the collective evidence and application of the ACMG criteria, the p.Gln79Arg variant is classified as pathogenic for Noonan syndrome. -
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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 - Loss of function and gain of function are known mechanisms of disease in this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines (MIM#151100) are associated with loss of function while Noonan syndrome 1 (MIM#163950) is associated with gain of function (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity and associated with Noonan syndrome (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Gln79His): 1 heterozygote, 0 homozygotes). (I) 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) within the N terminal SH2 domain (Decipher, NCBI). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Gln79Lys) and p.(Gln79Pro) variants have been reported in individuals with Noonan syndrome (PMID: 12960218; ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least ten individuals diagnosed with Noonan syndrome and has been classified as pathogenic by multiple clinical diagnostic laboratories (PMIDs: 16358218, 32164556; ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:7
In vitro expression of PTPN11-Q79R in cardiac cell cushions from chick embryos resulted in increased phosphatase activity and significantly increased outgrowth of cushion cells compared to wild-type protein expression (Krenz et al., 2005); Not observed 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; Located in the N-SH2 domain (Gelb 2018); This variant is associated with the following publications: (PMID: 22848035, 19017799, 17641779, 11704759, 24803665, 17020470, 16987887, 26855057, 11992261, 29396779, 12529711, 16166557, 19251646, 26607044, 22681964, 27521173, 27348588, 26817465, 12634870, 29084544, 29766225, 30417923, 30050098, 29907801, 31219622, 31560489, 32164556, 33318624, 34008892, 34006472, 35440950, 35178568, 29493581) -
PP2, PP3, PM1, PM2_supporting, PS2, PS3, PS4 -
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Noonan syndrome Pathogenic:3
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The p.Gln79Arg variant in PTPN11 has been reported in >30 individuals with clini cal features of Noonan syndrome and segregated with disease in >10 affected rela tives (Tartaglia 2001, Tartaglia 2002, Schollen 2003, Musante 2003, Yoshida 2004 , Zenker 2004, Chan 2006, Bertola 2006, LMM unpublished data). This variant has also occurred de novo in multiple affected individuals (LMM unpublished data). I t has not been identified in large population studies. In-vivo animal models and in-vitro studies provide evidence that the p.Gln79Arg variant impacts protein f unction (Krenz 2005, Nakamura 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant man ner based upon segregation studies, de novo occurrences in affected individuals, extremely low frequency in the general population, and functional evidence. -
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PTPN11-related disorder Pathogenic:2
This variant has been previously reported as a heterozygous change in patients with Noonan syndrome (PMID: 11704759, 11992261, 12529711, 12634870, 17020470, 22848035). This variant is located in a mutational hotspot for pathogenic variants associated with Noonan syndrome. Pathogenic missense variants at the same amino acid residue (p.Gln79Pro) and nearby amnio acid residues (p.Glu76Asp, p.Glu76Gln, p.Glu76Gly, p.Glu76Val) have been reported in association with Noonan syndrome (PMID: 12960218, 24803665, 3279447, 20308328). Functional studies showed that the c.236A>G (p.Gln79Arg) variant is a gain-of-function variant that induces an increase of phosphatase activity and endocardial cushion growth (PMID: 16166557, 15834506). Animal studies in mice showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects when the c.236A>G (p.Gln79Arg) variant is present (PMID: 17641779). The c.236A>G (p.Gln79Arg) variant is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. 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.236A>G (p.Gln79Arg) variant is classified as Pathogenic. -
The PTPN11 c.236A>G variant is predicted to result in the amino acid substitution p.Gln79Arg. This variant has been identified in many individuals with Noonan syndrome (Tartaglia et al. 2001. PubMed ID: 11704759; Tartaglia et al. 2006. PubMed ID: 16358218; Karbach et al. 2012. PubMed ID: 22848035; van Trier et al. 2016. PubMed ID: 27521173; Xu et al. 2017. PubMed ID: 29084544; Athota et al. 2020. PubMed ID: 32164556). In one family it was found to segregate in 3 affected individuals (Tartaglia et al. 2001. PubMed ID: 11704759) and has been noted as a de novo event in at least two cases (Karbach et al. 2012. PubMed ID: 22848035; Fan et al. 2021. PubMed ID: 34006472). This variant has been interpreted as pathogenic by multiple clinical labs in the ClinVar database. 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. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
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PM2_Supporting+PS2_Supporting+PS4+PP1_Strong+PS3 -
Noonan syndrome 3 Pathogenic:1
Variant summary: The PTPN11 c.236A>G (p.Gln79Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. It is located at N-SH2 domain of the protein (InterPro) which is a known functionally important domain in PTPN11 protein. This variant is absent in 121794 control chromosomes. This variant has been widely reported as a pathogenic variant in literature found in many Noonan Syndrome (NS) and/or Noonan Syndrome and Related Conditions (NSRD), including reports of de novo occurrences and co-segregation with disease (Tartaglia_2001, Schollen_2003, Niihori_2005, Ezquieta_2012, Karback_2012). In vitro studies show that this mutant results in significantly elevated phosphatase activity and endocardial cushion growth (Krenz_2005). Furthermore, in vivo mice expression model showed that this mutant leads to embryonic lethality and the embryonic hearts showed altered cardiomyocyte cell cycling ventricular noncompaction, and ventricular septal defects. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2 (Nakamura_2007). Another variant at the same residue, p.Q79K, has also been reported in NSRD patients (PMIDs: 12960218, 22848035, 16358218) and is classified as likely pathogenic by a clinical lab in ClinVar. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.236A>G (p.Q79R) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from an A to G substitution at nucleotide position 236, causing the glutamine (Q) at amino acid position 79 to be replaced by an arginine (R). This clinical significance of this variant is unclear for metachondromatosis; however, it would be expected to be causative of PTPN11-related RASopathy based on mechanism of disease. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation segregated in 3 individuals with Noonan syndrome and was absent from 2 unaffected individuals in one family (Tartaglia, 2001); it was also identified in a sporadic case (Tartaglia, 2001) and de novo in another affected individual (Karbach, 2012). This amino acid position is highly conserved in available vertebrate species. Activity studies in rat neonatal cardiomyocytes showed this alteration results in a gain-of-function of the protein, with a 4.5 times higher activity compared to wild type (Krenz, 2005). 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 glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 79 of the PTPN11 protein (p.Gln79Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11704759, 11992261, 12529711, 12634870, 17020470, 22848035). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13340). 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: 16166557, 17641779, 19017799). For these reasons, this variant has been classified as Pathogenic. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at