rs397507547

Positions:

• chr12-112489086-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PP2 PM6_Strong PS4_Moderate PS3

This summary comes from the ClinGen Evidence Repository: The 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220140/MONDO:0018997/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:33
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1510A>G	p.Met504Val	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1522A>G	p.Met508Val	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1507A>G	p.Met503Val	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1519A>G	p.Met507Val	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1510A>G	p.Met504Val	missense_variant	13/16	1	NM_002834.5	ENSP00000340944	A1

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

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

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

Submissions by phenotype

Noonan syndrome 1 Pathogenic:13

Likely pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 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) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 18, 2021	The 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, no assertion criteria provided	research	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	Dec 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	The 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. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Pathogenic, criteria provided, single submitter	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics, Centre for Human Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 16, 2018	This 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, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Feb 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 22, 2019	- -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2022	Published 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 submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 09, 2020	PP2, PP3, PM6_Strong, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	The 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, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PTPN11: PS2:Very Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3 -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This 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 provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2016	Variant 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. -

Noonan syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 16, 2021	The 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. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PTPN11 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. -

Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Dec 01, 2023

- -

Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 25, 2019

PTPN11 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. -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

The 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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

The 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; izmárová 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
DEOGEN2	Pathogenic	0.90	.;D;.
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
MutationAssessor	Pathogenic	3.0	.;M;.
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

Other links and lift over

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