Menu
GeneBe

rs397507547

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.1510A>G(p.Met504Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PTPN11
NM_002834.5 missense

Scores

13
4
1

Clinical Significance

Pathogenic reviewed by expert panel P:33

Conservation

PhyloP100: 8.95
Variant links:
Genes affected
PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002834.5
PP2
Missense variant where missense usually causes diseases, PTPN11
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 12-112489086-A-G is Pathogenic according to our data. Variant chr12-112489086-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40562.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-112489086-A-G is described in Lovd as [Pathogenic]. Variant chr12-112489086-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112489086-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.1510A>G p.Met504Val missense_variant 13/16 ENST00000351677.7
PTPN11NM_001330437.2 linkuse as main transcriptc.1522A>G p.Met508Val missense_variant 13/16
PTPN11NM_001374625.1 linkuse as main transcriptc.1507A>G p.Met503Val missense_variant 13/16
PTPN11XM_011538613.3 linkuse as main transcriptc.1519A>G p.Met507Val missense_variant 13/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.1510A>G p.Met504Val missense_variant 13/161 NM_002834.5 A1Q06124-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251490
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000137
AC:
2
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:33
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Noonan syndrome 1 Pathogenic:13
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneFeb 16, 2015- -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:15834506, 17661820, 17020470, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15834506, PS3). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000397, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenJan 22, 2019- -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San DiegoMar 16, 2018This variant has been reported multiple times as pathogenic in the literature and by clinical laboratories in the ClinVar database (Variation ID: 40562) in individuals with Noonan Syndrome (PMID: 11704759 26242988 28911804 29703613). The variant is absent from the population database gnomAD, thus presumed to be rare. The p.Met504 residue is highly conserved among eukaryotes, and in silico algorithms predict that the valine substitution will have a damaging effect on protein function. Functional characterization of the p.Met504Val demonstrated altered PTPN11 phosphatase activity compared to wild-type protein (PMID: 16358218). Based on the combined evidence, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, National Health Laboratory Service/University of the Witwatersrand-- -
Pathogenic, no assertion criteria providedresearchInstitute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan UniversityDec 24, 2021- -
Pathogenic, criteria provided, single submittercase-controlGenetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital-- -
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics, Centre for Human Genetics-- -
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 17, 2024- -
Likely pathogenic, no assertion criteria providedresearchBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College HospitalMay 31, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyJun 18, 2021The PTPN11 c.1510A>G variant is classified as PATHOGENIC (PP2, PS2, PS3, PS4) The PTPN11 c.1510A>G variant is a single nucleotide change in exon 13 of the PTPN11 gene, which is predicted to change the amino acid methionine at position 504 in the protein to valine. This de novo variant has been previously reported in multiple individuals with Noonan syndrome (PMID:15834506, PMID:11704759, PMID:11992261, PMID:24150203) (PS3, PS4). This variant is located within the highly conserved PTP domain of the protein and functional studies show altered (increased) phosphatase activity compared with WT protein (PMID:15834506) (PS3, PP2). This variant has been reported in dbSNP (rs397507547), and is rare in population databases (gnomAD 1/251490 alleles). The variant has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40562). -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based 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 and are associated with Noonan syndrome (MIM#163950), LEOPARD syndrome (MIM#151100), and Metachondromatosis (MIM#156250). Gain of function variants are associated with Noonan Syndrome, while loss of function variants cause LEOPARD syndrome or metachondromatosis (PMID: 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 methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) [p.(Met504Ile):1 heterozygote, 0 homozygotes]. (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. It is located within one of the hotspots for pathogenic or likely pathogenic missense variants (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis using mammalian cell lines showed a 3-fold increase in phosphatase activity in p.(Met504Val) mutant cells relative to wild-type (PMID: 15834506). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) -
not provided Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 09, 2020PP2, PP3, PM6_Strong, PS3 -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 28, 2023The PTPN11 c.1510A>G; p.Met504Val variant (rs397507547) is reported in the literature in individuals affected with Noonan syndrome (Ferreira 2008, Ko 2008, Niihori 2005, Tartaglia 2001, Tartaglia 2002), and has been observed in familial (Hung 2007) and de novo cases (Ferreira 2005, Kingsmore 2019). This variant is also reported in the ClinVar database (Variation ID: 40562). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Hof 1998, Tartaglia 2001), and implicated in the destabilizing the inactive conformation of the protein (Tartaglia 2002). The methionine at codon 504 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). Functional analyses of the p.Met504Val protein show increased catalytic activity upon growth factor-mediated stimulation (Niihori 2005, Tartaglia 2006), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, this 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. Ferreira L et al. Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients. Clin Endocrinol (Oxf). 2008 69(3):426-31. PMID: 18331608. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 92(4): 441-450. PMID: 9491886. Hung C et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 106(2):169-72. PMID: 17339163. Kingsmore SF et al. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. PMID: 31564432. Ko J et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008 53(11-12):999-1006. PMID: 19020799. Niihori T et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. 2005 J Hum Genet. 50(4):192-202. PMID: 15834506. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. 2001 Nat Genet. 29(4):465-8. PMID: 11704759. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 70(6): 1555-1563. PMID: 11992261. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. PMID: 16358218. -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024PTPN11: PS2:Very Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3 -
Pathogenic, no assertion criteria providedclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 15, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 24, 2022Published functional studies demonstrate a damaging effect, resulting in increased phosphatase activity (Niihori et al., 2005); 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; Classified as pathogenic by the ClinGen RASopathy Expert Panel (ClinVar SCV000616376.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 24150203, 28483241, 28152038, 17661820, 15834506, 24803665, 17361219, 11704759, 26242988, 27521173, 28911804, 28607217, 29493581, 21407260, 26607044, 29703613, 29620724, 30355600, 30417923, 30050098, 29907801, 31219622, 31263281, 31560489, 31564432, 31324109, 32164556, 32824488, 31019026, 32410215, 33619735, 34006472, 33726816, 27535533) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 01, 2013- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareOct 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsApr 17, 2018- -
RASopathy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 21, 2016Variant summary: The c.1510A>G variant in PTPN11 gene is a missense change that alters a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant has been reported in multiple affected individuals as de novo occurrences as well as inherited from affected parents. The mutation lies within a region of the gene coding for the highly conserved PTP domain of the protein tyrosine phosphatase 11 and was shown to increase the phosphatase activity in functional studies. The variant is absent from the large control population dataset of ExAC. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 18, 2024This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 504 of the PTPN11 protein (p.Met504Val). This variant is present in population databases (rs397507547, gnomAD 0.0009%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 15834506, 17339163, 19077116, 21407260, 24150203). ClinVar contains an entry for this variant (Variation ID: 40562). 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: 16358218). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingBaylor Genetics-Variant classified using ACMG guidelines -
Noonan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 16, 2021The p.Met504Val variant in PTPN11 has been reported in at least 20 individuals with clinical features of Noonan syndrome and at least 1 individual with metachondromatosis. It has been reported as a de novo occurence in at least 2 cases of Noonan syndrome, 1 case of metachondromatosis and 1 case of ventricular septal defect (Tartaglia 2002 PMID: 11992261, Niihori 2005 PMID: 15834506, Hung 2007 PMID: 17339163, Ferreira 2008 PMID: 18331608, Ko 2008 PMID: 19020799, Maddirevula 2018 PMID: 29620724, LMM data). It has also been identified in 0.0009% (1/113766) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397507547); however, this frequency is low enough to be consistent with the prevalence and variable expressivity of Noonan syndrome. This variant was classified as Pathogenic on July 15, 2019 by the ClinGen-approved RASopathy Variant Curation Expert Panel (Variation ID 40562). Computational prediction tools and conservation analysis suggest that the p.Met504Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function and reduce phosphatase activity (Niihori 2005 PMID: 15834506, Tartaglia 2006 PMID: 16358218). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM6_Strong, PS3_Moderate, PP3, PP2. -
Pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 03, 2017The c.1510A>G (p.Met504Val) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients and 3 independent occurrences in patients with clinical features of a RASopathy (PM6_Strong, PS4; GeneDx internal data; GTR Lab ID: 26957; SCV000057454.12; PMID: 15834506, 17661820, 17020470). In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function (PS3; PMID: 15834506). 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 (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Met504Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM6_Strong, PS4_Moderate, PP2, PP3. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021PTPN11 NM_002834.4 exon13 c.1510A>G p.Met504Val: This variant has been reported in the literature in multiple individuals with Noonan syndrome (Selected publications: Tartaglia 2001 PMID11704759, Jongsman 2011 PMID21407260, van Trier 2016 PMID38621173, Leach 2018 PMID 30050098). This variant is present in 0.0008% (1/113766) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-112926890-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as pathogenic, including the ClinGen RASopathy Variant Curation Expert Panel (Variation ID: 40562). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies support that this variant will impact the protein by causing an increase in phosphatase activity (Niihori 2005 PMID15834506). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
PTPN11-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 25, 2023The PTPN11 c.1510A>G variant is predicted to result in the amino acid substitution p.Met504Val. This variant has been identified in at least thirteen individuals with either familial or sporadic Noonan syndrome (Tartaglia et al. 2001. PubMed ID: 11704759; Tartaglia et al. 2002. PubMed ID: 11992261; Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218; Hung et al. 2007. PubMed ID: 17339163; Pierpont et al. 2009. PubMed ID: 19077116; Jongmans et al. 2011. PubMed ID: 21407260), including a de novo event in at least one individual (Table S1 - Maddirevula et al. 2018. PubMed ID: 29620724). Functional studies demonstrate increased phosphatase activity, consistent with a gain-of-function mechanism (Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218). Multiple laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40562/). Additionally, a different amino acid substitution affecting the same amino acid (p.Met504Leu) has been reported in an individual with Noonan syndrome (Narayanan et al. 2017. PubMed ID: 28607217). This variant is interpreted as pathogenic. -
Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1
Pathogenic, criteria provided, single submitterresearchLaan Lab, Human Genetics Research Group, University of TartuDec 01, 2023- -
Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoOct 25, 2019PTPN11 NM_002834.4 exon13 c.1510A>G p.Met504Val: This variant has been reported in the literature in multiple individuals with Noonan syndrome (Selected publications: Tartaglia 2001 PMID11704759, Jongsman 2011 PMID21407260, van Trier 2016 PMID38621173, Leach 2018 PMID 30050098). This variant is present in 0.0008% (1/113766) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-112926890-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as pathogenic, including the ClinGen RASopathy Variant Curation Expert Panel (Variation ID: 40562). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies support that this variant will impact the protein by causing an increase in phosphatase activity (Niihori 2005 PMID15834506). In summary, this variant is classified as pathogenic based on the data above. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 27, 2021The p.M504V pathogenic mutation (also known as c.1510A>G), located in coding exon 13 of the PTPN11 gene, results from an A to G substitution at nucleotide position 1510. The methionine at codon 504 is replaced by valine, an amino acid with highly similar properties. This mutation has been identified in multiple individuals with Noonan syndrome, including de novo occurrences (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Hung CS et al. J. Formos. Med. Assoc., 2007 Feb;106:169-72; izm&aacute;rov&aacute; M et al. Ann. Hum. Genet., 2016 Jan;80:50-62; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Caiazza M et al. Genes (Basel). 2020 08;11(8). In vitro analysis of this alteration demonstrated mild phosphatase activation, a three-fold increased compared to wildtype (Niihori T et al. J. Hum. Genet., 2005 Apr;50:192-202). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
Cadd
Pathogenic
29
Dann
Uncertain
1.0
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.87
D
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-3.5
D;.;.
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0020
D;.;.
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.95
MutPred
0.94
Gain of catalytic residue at M504 (P = 0.01);.;.;
MVP
0.99
MPC
1.9
ClinPred
0.97
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397507547; hg19: chr12-112926890; COSMIC: COSV61012722; COSMIC: COSV61012722; API