chr12-112477720-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.923A>G(p.Asn308Ser) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N308D) has been classified as 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.923A>G | p.Asn308Ser | missense_variant | Exon 8 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.923A>G | p.Asn308Ser | missense_variant | Exon 8 of 15 | 5 | ENSP00000489597.1 | |||
| PTPN11 | ENST00000635652.1 | c.-212A>G | upstream_gene_variant | 3 | ENSP00000489541.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:13Other:1
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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 associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (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) (3 heterozygotes, 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 (PMID: 11992261) within the protein tyrosine phosphatase domain (PMID: 26817465). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes, p.(Asn308Asp) and p.(Asn308Thr), have been reported in multiple individuals with Noonan syndrome 1 (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most commonly reported variants in this gene in individuals with Noonan syndrome 1. (SP) 1102 - Strong phenotype match for this individual. (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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The PTPN11 c.923A>G variant is classified as a PATHOGENIC variant (PS1, PS3, PS4, PP3) The variant is a single nucleotide change from an adenine to a guanine at position 923 which is predicted to change the Asparagine at position 308 in the protein to Serine. The variant is in exon 8 and is located in protein domains: protein-tyrosine phosphatase (receptor/non-receptor type) of the PTPN11 gene. This variant is a recurrent PTPN11 variant, previously reported in on patient in our laboratory and in multiple individuals with Noonan syndrome across multiple publications, including Tartaglia et al., 2002 (PMID: 11992261) (PS4). This variant is in dbSNP (rs121918455) but is absent from population databases. Other variants at this codon (p.Asn308Asp, p.Asn308Thr) have been previously reported in individuals with Noonan syndrome and are considered pathogenic (PS1). In vitro functional studies have shown that this variant alters substrate specificity and increased catalytic activity relative to the wildtype protein (PMID:15987685) (PS3). The vaviants has been reported in ClinVar (Variation ID: 13327) and HGMD (Accession: CM021135) as pathogenic. Computational predictions support a deleterious effect on the gene or gene product (PP3). -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.013%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 33473208). In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.22 (>=0.2, moderate evidence for spliceogenicity)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000932944 /PMID: 33473208 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 33473208). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33473208). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
This variant identified in a very young patient diagnosed with the Noonan syndrome has already been reported to cause this syndrome. -
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not provided Pathogenic:10
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Published functional studies demonstrate a damaging effect showing that the variant impacts substrate specificity of the catalytic site (Keilhack et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 30417923, 32369273, 18854871, 11992261, 27626068, 26918529, 11704759, 26817465, 25912702, 29084544, 28991257, 30050098, 20718194, 30842647, 29907801, 31219622, 31560489, 32164556, 31370276, 32037394, 15987685, 33686258, 33318624, 33300679, 33673806, 32368696, 33442022, 29493581, 16053901, 9491886) -
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The PTPN11 c.923A>G; p.Asn308Ser variant (rs121918455) is reported in the literature in numerous individuals affected with Noonan syndrome (Demir 2010, Ezquieta 2012, Lee 2011, Lepri 2014, Tartaglia 2006, Tartaglia 2002, Xu 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13327) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional analyses demonstrate that the Asn308Ser variant has altered substrate specificity and increased catalytic activity relative to the wildtype protein (Keilhack 2005), consistent with established disease mechanisms of Noonan syndrome (Tartaglia 2001). Additionally, other variants at this codon (c.922A>G; p.Asn308Asp, c.923A>C; p.Asn308Thr) have been reported in individuals with Noonan syndrome and are considered pathogenic (Ezquieta 2012, Lee 2011, Lepri 2014, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006). Based on available information, the p.Asn308Ser variant is considered pathogenic. REFERENCES Demir K et al. A mother and son with Noonan syndrome resulting from a PTPN11 mutation: first report of molecularly proven cases from Turkey. Turk J Pediatr. 2010 May-Jun;52(3):321-4 Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Lee BH et al. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011 Dec;159(6):1029-35. Lepri FR et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. 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. 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. 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. Xu S et al. Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders. BMC Med Genomics. 2017 Oct 30;10(1):62. -
Noonan syndrome Pathogenic:5
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Mutations in this gene can cause Noonan syndrome (NS), a class of autosomal dominant disorders, which can be clinically characterized by a peculiar facial appearance (e.g., wide eye spacing, ptosis, medial canthus, low ear position, and high palpebral arches), mild mental retardation, short necks, short stature, abnormalities of the cardiovascular system, disorders of the genitourinary system, and abnormalities of the hematologic system. The disease is caused by functionally acquired mutations in PTPN11 in about half of the cases. -
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The p.Asn308Ser variant has previously been associated with the clinical feature s of Noonan syndrome and Noonan syndrome associated with multiple giant-cell les ions in bone (Ko 2008, Tartaglia 2002, Pierpont 2009, Sarkozy 2003, Tartaglia 20 05). This variant has been observed to have occurred de novo in sporadic cases a nd to segregate with clinical features in familial cases. Variants affecting pos ition 308 (p.Asn308Ser and p.Asn308Asp) are the most frequently identified patho genic PTPN11 mutations in individuals with clinical features of Noonan syndrome in our laboratory. In summary, this variant meets our criteria to be classified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon seg regation studies, de novo occurrence, and absence from controls. -
LEOPARD syndrome 1 Pathogenic:2
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP2,PP4. -
The missense c.923A>G (p.Asn308Ser) variant in PTPN11 gene has been reported in heterozygous state in multiple individuals affected with PTPN11-related disorders (Digilio et al., 2013; Lepri et al., 2014; Loddo et al., 2015). It has also been observed to segregate with disease in related individuals (Digilio et al., 2013). Functional studies demonstrate a damaging effect showing that the variant impacts substrate specificity of the catalytic site (Keilhack et al., 2005). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Asn308Ser in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 308 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic -
PTPN11-related disorder Pathogenic:2
The PTPN11 c.923A>G variant is predicted to result in the amino acid substitution p.Asn308Ser. This variant has been well-documented to be causative for Noonan Syndrome (see for example - Tartaglia et al. 2002. PubMed ID: 11992261). This variant was found to segregate in a large multi-generation pedigree (Tartaglia et al. 2002. PubMed ID: 11992261) and has been reported as a de novo variant in an individual with congenital heart defects (Jin et al. 2017. PubMed ID: 28991257, Table S9). Functional studies of this variant demonstrate increased catalytic activity and altered substrate specificity compared to wild type PTPN11 (Keilhack et al. 2005. PubMed ID: 15987685). Additionally, different amino acid substitutions (p.Asn308Asp, p.Asn308Thr) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic by multiple clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/13327/). This variant is interpreted as pathogenic. -
This variant has been observed as a heterozygous change in multiple individuals with Noonan Syndrome and shown to segregate with disease in several families (PMID: 11992261, 20718194, 25912702, 24451042, 29907801). Functional studies of p.Asn308Ser have shown that it alters substrate specificity at the catalytic site (PMID: 15987685). A different missense substitution at this codon (p.Asn308Asp) has also been determined to be pathogenic (PMID: 11992261). ClinVar contains an entry for this variant (Variation ID: 13327).It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.923A>G, p.Asn308Ser variant is classified as Pathogenic. -
RASopathy Pathogenic:2
Variant classified using ACMG guidelines -
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 308 of the PTPN11 protein (p.Asn308Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 19077116, 20718194, 22781091, 24451042, 25595571). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13327). 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%. This variant disrupts the p.Asn308 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261). 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. -
LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
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Noonan syndrome 3 Pathogenic:1
Variant summary: The PTPN11 c.923A>G (p.Asn308Ser) variant involves the alteration of a conserved nucleotide. Residue Asn308 is buried within the PTP domain, and is reported as the most common residue affected in NS patients(N308D and N308S). 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). However, functional assays suggest that this variant alters substrate specificity (Keilhack_JBC_2005), and N308S SHP-2-expressing fetal liver cells also displayed a hypersensitive pattern of CFU-GM colony growth in response to GM-CSF (Schubbert_Blood_2005). This variant has been reported in numerous patients with NS and related conditions and was absent in 122002 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
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Noonan syndrome and Noonan-related syndrome Pathogenic:1
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Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at