VCV000040566.56 - ClinVar

NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu)

Variation ID: 40566 Accession: VCV000040566.56

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.13 12: 112489104 (GRCh38) [ NCBI UCSC ] 12: 112926908 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Oct 20, 2024	Nov 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.1528C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002825.3:p.Gln510Glu	missense
NM_001330437.2:c.1540C>G	NP_001317366.1:p.Gln514Glu	missense
NM_001374625.1:c.1525C>G	NP_001361554.1:p.Gln509Glu	missense
NC_000012.12:g.112489104C>G
NC_000012.11:g.112926908C>G
NG_007459.1:g.75373C>G
LRG_614:g.75373C>G
LRG_614t1:c.1528C>G

... more HGVS ... less HGVS

Protein change

Q510E, Q514E, Q509E

Other names

p.Q510E:CAG>GAG

Canonical SPDI

NC_000012.12:112489103:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA273420 dbSNP: rs397507549 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PTPN11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	970	982

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
RASopathy	Pathogenic (2)	criteria provided, single submitter	Nov 27, 2023	RCV000033553.16
LEOPARD syndrome 1	not provided (1)	no classification provided	-	RCV000055888.6
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 21, 2023	RCV000210041.31
Noonan syndrome 3	Pathogenic (1)	criteria provided, single submitter	Mar 7, 2016	RCV000589512.2
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Sep 6, 2019	RCV000619738.4
Noonan syndrome 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 23, 2023	RCV000679882.7
Noonan syndrome Noonan syndrome with multiple lentigines	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2012	RCV000824751.5
PTPN11-related disorder	Pathogenic (1)	criteria provided, single submitter	-	RCV004545736.1
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2020	RCV002251945.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000265845.1 First in ClinVar: Mar 18, 2016 Last updated: Mar 18, 2016	Publications: PubMed (2) PubMed: 15889278‚ 16733669 Number of individuals with the variant: 1 Clinical Features: Prenatal onset hypertrophic cardiomyopathy (present) , Dysplastic pulmonary valve (present) , Hypertelorism (present) Age: 0-9 years Sex: male
Pathogenic (May 21, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000057458.14 First in ClinVar: Apr 04, 2013 Last updated: May 27, 2023	Comment: Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012); Missense variants in this gene are often … (more) Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29696744, 30732632, 30384889, 35050212, 25708222, 21803945, 22058153, 21677813, 24935154, 19582499, 26742426, 15889278, 23673659, 16733669, 19273734, 16358218, 18241070, 28973083, 21910226, 20954246, 25724491, 25359717, 30050098, 29907801, 31219622, 31712860, 32164556, 31965297, 31370276, 32573669, 33318624) (less)
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000776867.7 First in ClinVar: Apr 09, 2018 Last updated: Feb 14, 2024	Publications: PubMed (17) PubMed: 15889278‚ 16733669‚ 19077116‚ 19582499‚ 20954246‚ 21677813‚ 22190897‚ 25708222‚ 21803945‚ 22058153‚ 23673659‚ 24935154‚ 26742426‚ 2057894‚ 15520399‚ 15690106‚ 16358218 Comment: This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 510 of the PTPN11 protein … (more) This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 510 of the PTPN11 protein (p.Gln510Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and/or Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) (PMID: 15889278, 16733669, 19077116, 19582499, 20954246, 21677813, 22190897, 25708222). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40566). 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: 21803945, 22058153, 23673659, 24935154, 25708222, 26742426). This variant disrupts the p.Gln510 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2057894, 15520399, 15690106, 16358218). 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. (less)
Pathogenic (Jun 14, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Noonan syndrome Noonan syndrome with multiple lentigines Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203937.5 First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019	Publications: PubMed (10) PubMed: 16358218‚ 16733669‚ 15889278‚ 18241070‚ 19273734‚ 19582499‚ 21677813‚ 21803945‚ 22058153‚ 21910226 Comment: The p.Gln510Glu variant in PTPN11 has been reported in >10 individuals with clin ical features of RASopathy disorders (Faienza 2009, Lehmann 2009, Tartaglia 2006 , … (more) The p.Gln510Glu variant in PTPN11 has been reported in >10 individuals with clin ical features of RASopathy disorders (Faienza 2009, Lehmann 2009, Tartaglia 2006 , Wakabayashi 2011, Digilio 2006, Ganigara 2011, Limongelli 2008, Takahashi 2005 , and LMM data). This variant has been reported to have occurred de novo in at l east one individual (Faienza 2009). Furthermore, animal models in mice have show n that this variant causes hypertrophic cardiomyopathy (Schramm 2012). In summar y, this variant meets criteria to be classified as pathogenic for RASopathy diso rder in an autosomal dominant manner. (less) Number of individuals with the variant: 11
Pathogenic (Dec 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523897.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PS2, PS4, PM2, PP2, PP3 Clinical Features: Thrombocytopenia (present) , Hypoglycemia (present) , Hypertelorism (present) , Hepatomegaly (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Cardiomyopathy (present) , … (more) Thrombocytopenia (present) , Hypoglycemia (present) , Hypertelorism (present) , Hepatomegaly (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Cardiomyopathy (present) , Cardiac arrhythmia (present) , Abnormal heart valve morphology (present) , Thrombocytopenia (present) , Hypoglycemia (present) , Hypertelorism (present) , Hepatomegaly (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Cardiomyopathy (present) , Cardiac arrhythmia (present) , Abnormal heart valve morphology (present) , Thrombocytopenia (present) , Hypoglycemia (present) , Hypertelorism (present) , Hepatomegaly (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Cardiomyopathy (present) , Cardiac arrhythmia (present) , Abnormal heart valve morphology (present) , Thrombocytopenia (present) , Hypoglycemia (present) , Hypertelorism (present) , Hepatomegaly (present) , Downslanted palpebral fissures (present) , Depressed nasal bridge (present) , Cardiomyopathy (present) , Cardiac arrhythmia (present) , Abnormal heart valve morphology (present) (less) Geographic origin: Brazil
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807271.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (6) PubMed: 25326635‚ 15889278‚ 21677813‚ 21803945‚ 22058153‚ 19582499 Comment: This variant has been previously reported as disease-causing and was found once in our laboratory in a 3-month-old male with cardiovascular disease (dysplastic pulmonary valve, … (more) This variant has been previously reported as disease-causing and was found once in our laboratory in a 3-month-old male with cardiovascular disease (dysplastic pulmonary valve, severe pulmonic stenosis, thickened aortic valve leaflets, abnorma mitral valve, ventricular hypertrophy), microcephaly, failure to thrive, dysmorphisms (hypertelorism, down-slanting palpebral fissures, retrgnathia, low-set posteriorly rotated ears), left pelvic kidney (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PTPN11-Related Disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046160.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant has been reported in the literature in individuals affected with Noonan syndrome with multiple lentigines (NSML, also referred to as LEOPARD syndrome) or … (more) This variant has been reported in the literature in individuals affected with Noonan syndrome with multiple lentigines (NSML, also referred to as LEOPARD syndrome) or Noonan syndrome, also as a de novo alteration (PMID: 16733669, 22190897, 25708222, 21677813, 20954246, 15889278, 19582499, 19077116). In-vitro studies have shown that this missense change abolishes PTPN11 phosphatase activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222), and mouse models have demonstrated altered cardiac function (PMID: 22058153). The c.1528C>G (p.Gln510Glu) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1528C>G (p.Gln510Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants affecting the same amino acid residue, including a c.1530G>T (p.Gln510His), have been reported individuals with NSML or Noonan syndrome (PMID: 27193571, 21910226, 15520399, 16358218, 20578946, 15690106). 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.1528C>G (p.Gln510Glu) variant is classified as Pathogenic. (less)
Pathogenic (Mar 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247474.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 4
Pathogenic (Mar 07, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Noonan syndrome 3 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698058.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (9) PubMed: 20954246‚ 22058153‚ 25708222‚ 21677813‚ 18241070‚ 16358218‚ 22781091‚ 19077116‚ 18505544 Comment: Variant summary: The c.1528C>G in a PTPN11 gene alters a highly conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant has … (more) Variant summary: The c.1528C>G in a PTPN11 gene alters a highly conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant has been reported in multiple affected individuals with NSRD with early onset HCM. The variant is absent in control dataset of ExAC. Animal model studies concluded that cardiomyocyte-specific expression of Q510E-Shp2 was sufficient to induce the HCM phenotype. In addition, other variants affecting codon Q510 have been reported in pts with NSRD. Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic. (less)
Pathogenic (Feb 14, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225834.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jul 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: de novo	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV001244986.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020	Comment: A heterozygous missense variant, NM_002834.3(PTPN11):c.1528C>G, has been identified in exon 13 of 16 of the PTPN11 gene. The variant is predicted to result in a … (more) A heterozygous missense variant, NM_002834.3(PTPN11):c.1528C>G, has been identified in exon 13 of 16 of the PTPN11 gene. The variant is predicted to result in a minor amino acid change from a glutamine to a glutamic acid at position 510 of the protein, NP_002825.3(PTPN11):p.(Gln510Glu). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the protein tyrosine phosphatase functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has previously been described multiple times as pathogenic in patients with Noonan syndrome and Noonan syndrome with multiple letigines with reported de novo cases (ClinVar). Additionally, functional analysis of cardiomyocyte cell lines demonstrated significant attenuation of myofibrillogenesis and increased proliferation, whilst mice overexpressing this variant showed increased cardiomyocyte size, heart-to-body weight ratios, interventricular septum thickness, cardiomyocyte disarray, thickened ventricular walls and depressed contractile function (Ishida, H., et al. (2011), Schramm, C., et al. (2012)). Three alternate variants in the same codon, p.(Gln510Arg), p.(Gln510Pro) and p.(Gln510His) have been reported multiple times in patients with Noonan syndrome and Noonan syndrome with multiple letigines (ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less) Number of individuals with the variant: 1 Clinical Features: Hypertrophic cardiomyopathy (present) Secondary finding: no
Pathogenic (Mar 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV003925556.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023 Comment: PMID:25741868 (PS3, PS4, PM2, PM5, PM6, PP3)
Pathogenic (Sep 06, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000739999.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Publications: PubMed (18) PubMed: 15889278‚ 16358218‚ 16733669‚ 18241070‚ 19273734‚ 19582499‚ 20954246‚ 21677813‚ 21803945‚ 21910226‚ 22058153‚ 23673659‚ 24935154‚ 25359717‚ 25708222‚ 25724491‚ 26742426‚ 30732632 Comment: The p.Q510E pathogenic mutation (also known as c.1528C>G), located in coding exon 13 of the PTPN11 gene, results from a C to G substitution at … (more) The p.Q510E pathogenic mutation (also known as c.1528C>G), located in coding exon 13 of the PTPN11 gene, results from a C to G substitution at nucleotide position 1528. The glutamine at codon 510 is replaced by glutamic acid, an amino acid with highly similar properties. This mutation has been reported in numerous individuals with Noonan syndrome or Noonan syndrome with multiple lentigines, at least two of which are likely of de novo origin (Takahashi K et al. Eur. J. Pediatr. 2005;164:497-500; Digilio MC et al. Eur. J. Pediatr. 2006;165:803-5; Faienza MF et al. Pediatr Cardiol. 2009;30:1012-5; Ganigara M et al. Ann Pediatr Cardiol. 2011;4:74-6; Hahn A et al. Am. J. Med. Genet. A. 2015;167A:744-51; Sayeed M et al. Int J clin Cardiol. 2015;2:052-6; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29). In addition, assays in both in vitro and in vivo models have demonstrated disrupted PTPN11 protein function for p.Q510E, and resultant hypertrophic cardiomyopathy (Ishida H et al. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1531-9; Schramm C et al. Am. J. Physiol. Heart Circ. Physiol. 2012;302:H231-43; Yu ZH et al. Biochemistry. 2014;53:4136-51; Noda S et al. Biochem. Biophys. Res. Commun. 2016;469:1133-9). Based on the supporting evidence, p.Q510E is interpreted as a disease-causing mutation. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196655.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Publications: PubMed (4) PubMed: 15889278‚ 16733669‚ 19582499‚ 21677813 Comment: Variant classified using ACMG guidelines
not provided (-)	no classification provided Method: literature only	LEOPARD syndrome 1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086894.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301557 BookShelf: NBK1383 BookShelf: NBK1383
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Comment:

Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29696744, 30732632, 30384889, 35050212, 25708222, 21803945, 22058153, 21677813, 24935154, 19582499, 26742426, 15889278, 23673659, 16733669, 19273734, 16358218, 18241070, 28973083, 21910226, 20954246, 25724491, 25359717, 30050098, 29907801, 31219622, 31712860, 32164556, 31965297, 31370276, 32573669, 33318624)

Comment:

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 510 of the PTPN11 protein (p.Gln510Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and/or Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) (PMID: 15889278, 16733669, 19077116, 19582499, 20954246, 21677813, 22190897, 25708222). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40566). 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: 21803945, 22058153, 23673659, 24935154, 25708222, 26742426). This variant disrupts the p.Gln510 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2057894, 15520399, 15690106, 16358218). 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.

Comment:

The p.Gln510Glu variant in PTPN11 has been reported in >10 individuals with clin ical features of RASopathy disorders (Faienza 2009, Lehmann 2009, Tartaglia 2006 , Wakabayashi 2011, Digilio 2006, Ganigara 2011, Limongelli 2008, Takahashi 2005 , and LMM data). This variant has been reported to have occurred de novo in at l east one individual (Faienza 2009). Furthermore, animal models in mice have show n that this variant causes hypertrophic cardiomyopathy (Schramm 2012). In summar y, this variant meets criteria to be classified as pathogenic for RASopathy diso rder in an autosomal dominant manner.

Comment:

This variant has been previously reported as disease-causing and was found once in our laboratory in a 3-month-old male with cardiovascular disease (dysplastic pulmonary valve, severe pulmonic stenosis, thickened aortic valve leaflets, abnorma mitral valve, ventricular hypertrophy), microcephaly, failure to thrive, dysmorphisms (hypertelorism, down-slanting palpebral fissures, retrgnathia, low-set posteriorly rotated ears), left pelvic kidney

Comment:

This variant has been reported in the literature in individuals affected with Noonan syndrome with multiple lentigines (NSML, also referred to as LEOPARD syndrome) or Noonan syndrome, also as a de novo alteration (PMID: 16733669, 22190897, 25708222, 21677813, 20954246, 15889278, 19582499, 19077116). In-vitro studies have shown that this missense change abolishes PTPN11 phosphatase activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222), and mouse models have demonstrated altered cardiac function (PMID: 22058153). The c.1528C>G (p.Gln510Glu) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1528C>G (p.Gln510Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants affecting the same amino acid residue, including a c.1530G>T (p.Gln510His), have been reported individuals with NSML or Noonan syndrome (PMID: 27193571, 21910226, 15520399, 16358218, 20578946, 15690106). 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.1528C>G (p.Gln510Glu) variant is classified as Pathogenic.

Comment:

Variant summary: The c.1528C>G in a PTPN11 gene alters a highly conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant has been reported in multiple affected individuals with NSRD with early onset HCM. The variant is absent in control dataset of ExAC. Animal model studies concluded that cardiomyocyte-specific expression of Q510E-Shp2 was sufficient to induce the HCM phenotype. In addition, other variants affecting codon Q510 have been reported in pts with NSRD. Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.

Comment:

A heterozygous missense variant, NM_002834.3(PTPN11):c.1528C>G, has been identified in exon 13 of 16 of the PTPN11 gene. The variant is predicted to result in a minor amino acid change from a glutamine to a glutamic acid at position 510 of the protein, NP_002825.3(PTPN11):p.(Gln510Glu). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the protein tyrosine phosphatase functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has previously been described multiple times as pathogenic in patients with Noonan syndrome and Noonan syndrome with multiple letigines with reported de novo cases (ClinVar). Additionally, functional analysis of cardiomyocyte cell lines demonstrated significant attenuation of myofibrillogenesis and increased proliferation, whilst mice overexpressing this variant showed increased cardiomyocyte size, heart-to-body weight ratios, interventricular septum thickness, cardiomyocyte disarray, thickened ventricular walls and depressed contractile function (Ishida, H., et al. (2011), Schramm, C., et al. (2012)). Three alternate variants in the same codon, p.(Gln510Arg), p.(Gln510Pro) and p.(Gln510His) have been reported multiple times in patients with Noonan syndrome and Noonan syndrome with multiple letigines (ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

The p.Q510E pathogenic mutation (also known as c.1528C>G), located in coding exon 13 of the PTPN11 gene, results from a C to G substitution at nucleotide position 1528. The glutamine at codon 510 is replaced by glutamic acid, an amino acid with highly similar properties. This mutation has been reported in numerous individuals with Noonan syndrome or Noonan syndrome with multiple lentigines, at least two of which are likely of de novo origin (Takahashi K et al. Eur. J. Pediatr. 2005;164:497-500; Digilio MC et al. Eur. J. Pediatr. 2006;165:803-5; Faienza MF et al. Pediatr Cardiol. 2009;30:1012-5; Ganigara M et al. Ann Pediatr Cardiol. 2011;4:74-6; Hahn A et al. Am. J. Med. Genet. A. 2015;167A:744-51; Sayeed M et al. Int J clin Cardiol. 2015;2:052-6; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29). In addition, assays in both in vitro and in vivo models have demonstrated disrupted PTPN11 protein function for p.Q510E, and resultant hypertrophic cardiomyopathy (Ishida H et al. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1531-9; Schramm C et al. Am. J. Physiol. Heart Circ. Physiol. 2012;302:H231-43; Yu ZH et al. Biochemistry. 2014;53:4136-51; Noda S et al. Biochem. Biophys. Res. Commun. 2016;469:1133-9). Based on the supporting evidence, p.Q510E is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Noonan Syndrome with Multiple Lentigines.	Adam MP	-	2022	PMID: 20301557
Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort.	Chen H	Orphanet journal of rare diseases	2019	PMID: 30732632
Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling.	Noda S	Biochemical and biophysical research communications	2016	PMID: 26742426
Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines.	Clay SA	American journal of physiology. Heart and circulatory physiology	2015	PMID: 25724491
Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog.	Hahn A	American journal of medical genetics. Part A	2015	PMID: 25708222
The Q510E mutation in Shp2 perturbs heart valve development by increasing cell migration.	Edwards MA	Journal of applied physiology (Bethesda, Md. : 1985)	2015	PMID: 25359717
Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations.	Yu ZH	Biochemistry	2014	PMID: 24935154
New approaches to prevent LEOPARD syndrome-associated cardiac hypertrophy by specifically targeting Shp2-dependent signaling.	Schramm C	The Journal of biological chemistry	2013	PMID: 23673659
Atrioventricular canal defect in patients with RASopathies.	Digilio MC	European journal of human genetics : EJHG	2013	PMID: 22781091
The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling.	Schramm C	American journal of physiology. Heart and circulatory physiology	2012	PMID: 22058153
RASopathies: Clinical Diagnosis in the First Year of Life.	Digilio MC	Molecular syndromology	2011	PMID: 22190897
Implantable cardioverter defibrillator for progressive hypertrophic cardiomyopathy in a patient with LEOPARD syndrome and a novel PTPN11 mutation Gln510His.	Wakabayashi Y	American journal of medical genetics. Part A	2011	PMID: 21910226
LEOPARD-type SHP2 mutant Gln510Glu attenuates cardiomyocyte differentiation and promotes cardiac hypertrophy via dysregulation of Akt/GSK-3β/β-catenin signaling.	Ishida H	American journal of physiology. Heart and circulatory physiology	2011	PMID: 21803945
LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation.	Ganigara M	Annals of pediatric cardiology	2011	PMID: 21677813
Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations.	Derbent M	American journal of medical genetics. Part A	2010	PMID: 20954246
PTPN11 gene mutation and severe neonatal hypertrophic cardiomyopathy: what is the link?	Faienza MF	Pediatric cardiology	2009	PMID: 19582499
IMAGE CARDIO MED. A patient with LEOPARD syndrome and PTPN11 mutation.	Lehmann LH	Circulation	2009	PMID: 19273734
Genotype differences in cognitive functioning in Noonan syndrome.	Pierpont EI	Genes, brain, and behavior	2009	PMID: 19077116
Leopard syndrome.	Sarkozy A	Orphanet journal of rare diseases	2008	PMID: 18505544
Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome.	Limongelli G	American journal of medical genetics. Part A	2008	PMID: 18241070
PTPN11 gene mutations: linking the Gln510Glu mutation to the "LEOPARD syndrome phenotype".	Digilio MC	European journal of pediatrics	2006	PMID: 16733669
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.	Tartaglia M	American journal of human genetics	2006	PMID: 16358218
A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.	Takahashi K	European journal of pediatrics	2005	PMID: 15889278
Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11.	Kalidas K	Journal of human genetics	2005	PMID: 15690106
PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience.	Keren B	Journal of medical genetics	2004	PMID: 15520399
[Secondary medicinal prevention of uncomplicated hypertension in an outpatient clinic].	Pavlov AA	Terapevticheskii arkhiv	1991	PMID: 2057894
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11	-	-	-	-
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Text-mined citations for rs397507549 ...

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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397507549 ...