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RASA1-Related Disorders

, MD, PhD, FACMG and , MD, FACMG.

Author Information

Initial Posting: ; Last Update: October 6, 2016.


Clinical characteristics.

RASA1-related disorders are characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences. Symptoms from intracranial AVMs/AVFs appear to occur early in life. Several individuals have RASA1-related Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft-tissue and skeletal growth of an affected limb).


The diagnosis of a RASA1-related disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in RASA1 identified by molecular genetic testing.


Treatment of manifestations: For capillary malformations that are of cosmetic concern, referral to a dermatologist. For AVMs and AVFs, the risks and benefits of intervention (embolization vs surgery) must be considered, usually with input from a multidisciplinary team (e.g., specialists in interventional radiology, neurosurgery, surgery, cardiology, and dermatology). For cardiac overload, referral to a cardiologist. For hemihyperplasia and/or leg-length discrepancy, referral to an orthopedist. Lymphangiography to evaluate for lymphatic malformations may be considered; compression stockings for those with evidence of lymphedema.

Surveillance: Repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident.

Evaluation of relatives at risk: Clarification of the genetic status of at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes.

Genetic counseling.

RASA1-related disorders are inherited in an autosomal dominant manner. About 70% of affected individuals have an affected parent; about 30% have a de novo pathogenic variant. Each child of an individual with a RASA1-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk and preimplantation genetic diagnosis are possible if the RASA1 pathogenic variant has been identified in an affected family member.

GeneReview Scope

RASA1-Related Disorders: Included Phenotypes 1
  • Capillary malformation-arteriovenous malformation syndrome
  • RASA1-related Parkes Weber syndrome

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Diagnostic criteria for CM-AVM syndrome has been proposed but not systematically evaluated [Orme et al 2013, Weitz et al 2015].

Suggestive Findings

RASA1-related disorders should be suspected in individuals who have any of the following:

  • Capillary malformations (CMs), the hallmark of RASA1-related disorders. CMs are generally:
    • Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
    • Composed of dilated capillaries in the papillary dermis [Hershkovitz et al 2008b];
    • Mostly localized on the face and limbs;
    • Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [Hershkovitz et al 2008a, Revencu et al 2008, Revencu et al 2013b].
  • Arteriovenous malformations (AVMs) / arteriovenous fistulas (AVFs) in soft tissue, bone, and brain which may be associated with overgrowth [Eerola et al 2003]
  • Parkes Weber syndrome (PKWS), a cutaneous capillary malformation associated with underlying multiple micro-AVFs and soft tissue and skeletal hypertrophy of the affected limb [Mulliken & Young 1988]

Establishing the Diagnosis

The diagnosis of a RASA1-related disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in RASA1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing including sequencing and analysis of large deletions and duplications. Sequence analysis of RASA1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

Table 1.

Molecular Genetic Testing Used in RASA1-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
RASA1Sequence analysis 361/66 (92%) 4
Gene-targeted deletion/duplication analysis 55/66 (~8%) 6

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Author, unpublished data


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


All five deletions were of exons [Author, unpublished data].

Clinical Characteristics

Clinical Description

The clinical manifestations of RASA1-related disorders have been described in more than 320 individuals in three publications with large cohorts (>20 cases) by Eerola et al [2003] (n=39), Revencu et al [2008] (n=101), and Revencu et al [2013b] (n=138), with insights from a number of other case series and case reports [Hershkovitz et al 2008a, Hershkovitz et al 2008b, Thiex et al 2010, Carr et al 2011, Buhl et al 2012, de Wijn et al 2012, Wooderchak-Donahue et al 2012, Burrows et al 2013, Català et al 2013, Durrington et al 2013, Kim et al 2015].

The most common manifestations in RASA1-related disorders and their frequency are capillary malformations (~97%), arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs) (~24%; 13% extra-central nervous system, 10% intra-central nervous system), and RASA1-related Parkes Weber syndrome (8%) [Revencu et al 2013b]. Note that because not all individuals with a RASA1-related disorder are likely to have had comprehensive imaging studies, the frequency of AVMs/AVFs is difficult to determine.

Significant intrafamilial and interfamilial variability has been described in terms of the existence and location of vascular malformations.

Capillary Malformations (CM)

CMs are multiple round or oval pink lesions mostly with a blanched halo. CMs can be present at birth and tend to increase in number over time

Arterial flow with Doppler ultrasound has been reported over the CMs [Kim et al 2015] and is hypothesized to be a manifestation of an underlying AVM. It is unclear if arterial flow abnormalities associated with the CMs can increase or develop over time.

Arteriovenous Malformations/Arteriovenous Fistulas (AVMs/AVFs)

Currently data on long-term development of AVMs/AVFs after initial screening are insufficient. Although it has been hypothesized that AVMs/AVFs may develop over time [Orme et al 2013], to date no individuals who had normal imaging screens have subsequently been reported to have developed AVMs/AVFs.

Intracranial AVMs/AVFs can manifest early in life [Revencu et al 2008, Revencu et al 2013b]. Vein of Galen aneurismal malformation and other intracranial AVMs have led to seizures, hydrocephalus, migraine headaches, and cardiac failure [Eerola et al 2003, Revencu et al 2008, Grillner et al 2016].

Revencu et al [2008] reported that most of the intracranial lesions were macrofistulas causing symptoms in infancy. However, this finding may be biased given that the identification of the AVMs/AVFs may be secondary to associated symptoms and that asymptomatic individuals may not have had the imaging studies needed to detect the lesions.

Extracranial AVMs and AVFs are typically reported in skin, muscle, and spine.

Although approximately 50% of AVMs/AVFs have been reported to be in the head/neck region [Revencu et al 2013b], the frequency of AVMs/AVFs in this location may be an overestimate because it is likely that imaging is preferentially performed in this region.

Symptomatic intraspinal AVMs resulting in neurologic deficits have been reported; MRI has identified intraspinous lesions requiring endovascular/surgical treatment [Thiex et al 2010].

AVMs/AVFs have not been commonly reported in viscera [Revencu et al 2008], a distinguishing difference from hereditary hemorrhagic telangiectasia (HHT).

Parkes Weber Syndrome

Limb overgrowth has been reported in both the upper and lower extremities in RASA1-related disorders. The overgrowth is typically noticeable in infancy and can range in severity. Most individuals with limb overgrowth fulfill the findings of Parkes Weber syndrome, defined by Revencu et al [2013b] as the presence of a capillary stain, bony and soft tissue hyperplasia, and multiple arteriolovenular microfistulas throughout an upper or lower extremity.


Cardiac overload/failure is a potential complication in individuals with significant fast flow lesions.

In particular, one third of individuals with RASA1-related Parkes Weber syndrome (PKWS) required cardiac follow up [Revencu et al 2008].

One of the persons reported in infancy by Eerola et al [2003] had an AVF between the left carotid artery and jugular vein that caused cardiac overload requiring treatment.

One woman with CM-AVM reported worsening of symptoms during pregnancy [Durrington et al 2013]. She developed pulmonary and peripheral edema with concern for high-output heart failure that resolved after pregnancy.

Non-immune hydrops fetalis due to an AVM has been reported [Overcash et al 2015].

Congenital heart defects have been reported in four individuals with RASA1-related disorders; however, this finding may be coincidental [Revencu et al 2008].

Lymphatic malformations have been reported in several individuals [de Wijn et al 2012, Burrows et al 2013, Macmurdo et al 2016], including one individual with RASA1-related Parkes Weber syndrome. Lymphangiography and near-infrared fluorescence lymphatic imaging showed abnormally dilated collecting lymphatics with sluggish flow in the unaffected limb, and tortuous lymphatics of the affected limb with lymphocele-like vesicles on the groin [Burrows et al 2013]. Whether these lymphatic abnormalities are progressive is not yet known.

Tumors. Individuals with RASA1-related disorders may theoretically be at increased risk for tumor development, but current review of the reported cases does not confirm this. Revencu et al [2008] reported several different types of tumors (e.g., optic glioma, lipoma, superficial basal cell carcinoma, angiolipoma, non-small-cell lung cancer, and vestibular schwannoma) in 44 families. However, in their larger series of 138 individuals, the only tumors reported were two common basal cell carcinomas in two individuals from the same family [Revencu et al 2013b].

Whether the rate of tumors is increased compared to the general population is still unknown, but it is likely not dramatically increased.

Other findings observed in a small number of individuals (but >1) include seizures, headaches, hydrocephalus, neurogenic bladder, varicosities, and hemangiomas. It is not clear if these findings are primary manifestations of a germline heterozygous RASA1 pathogenic variant or secondary complications of AVMs/AVFs.

Developmental delay and severe neurologic findings were reported in individuals with deletions encompassing RASA1 and MEF2C [Carr et al 2011], but it is thought that these findings are not secondary to deletion of RASA1. (See Differential Diagnosis.)

Genotype-Phenotype Correlations

Studies to date are insufficient to identify genotype-phenotype correlations.


Penetrance is 90%-99% based on the following studies:


Eerola et al [2003] named the phenotype caused by RASA1 pathogenic variants 'capillary malformation-arteriovenous malformation' (CM-AVM).


Prevalence of RASA1-related disorders is estimated at 1:100,000 in northern Europeans [Revencu et al 2008].

Differential Diagnosis

Table 2.

Disorders to Consider in the Differential Diagnosis of RASA1-Related Disorders

DisorderGene(s)MOIClinical Features in This Disorder
Overlapping w/RASA1-Related DisordersDistinguishing from RASA1-Related Disorders
Hereditary hemorrhagic telangiectasia (HHT)ACVRL 1
GDF2 1
ADMultiple arteriovenous malformations (AVMs) that lack intervening capillaries & result in direct connections between arteries & veinsMost common clinical manifestations: spontaneous & recurrent nosebleeds (epistaxis) & telangiectasia located on lips, nose, & hands. ~ 25% of patients may have GI bleeding later in life.
Sturge-Weber syndrome (SWS)
Intracranial vascular anomaly 3Segmental facial cutaneous vascular malformations (port-wine stains), seizures, & glaucoma 4
Klippel-Trenaunay-Weber syndrome (KTWS) 5
Capillary malformations & hypertrophy of the related bones & soft tissuesVascular malformations are typically low-flow lesions w/out high-flow AVMs 5
PTEN hamartoma tumor syndrome (PHTS) 7PTENADOvergrowth & fast flow lesionsVascular anomalies are usually intramuscular, are associated with ectopic fat, and severely disrupt tissue architecture 8. Tumor predisposition more prominent
Multiple cutaneous and mucosal venous malformations (VMCM)TEKADCutaneous venous malformations can be mistaken for capillary malformations.Small, multifocal bluish cutaneous and/or mucosal venous malformations, usually present at birth. New lesions appear w/time. Small lesions are usually asymptomatic; larger lesions can invade subcutaneous muscle & cause pain.
Hereditary glomuvenous malformations (GVM)
GLMNADCutaneous venous malformations can be mistaken for capillary malformations.Although clinically GVM can look like any venous malformation, they are more painful on palpation, only partially compressible, & usually not found in mucosa. 9 The lesions consist of glomus cells.
Familial aggregation is more common in hereditary GVM than in venous malformations generally.
Hereditary benign telangiectasia (HBT)
UnknownADSome of the cutaneous vascular malformations can be of similar size to those seen RASA1-related disorders.Lack of solid organ AVMs or genetic etiology

The known HHT-related genes are involved in the TGF-β/BMP signaling cascade.


Somatic mosaic mutation of GNAQ has been reported in individuals with Sturge-Weber syndrome [Shirley et al 2013].


Leptomeningeal angiomatosis most often involves the occipital and posterior parietal lobes.


No RASA1 pathogenic variants were identified in nine persons with SWS who represented simplex cases (i.e., a single occurrence in a family) [Zhou et al 2011] or in 37 individuals with SWS [Revencu et al 2013b].


Also referred to as Klippel-Trenaunay syndrome (KTS)


Diagnostic criteria for KTS have been proposed [Oduber et al 2008]. To date no RASA1 pathogenic variants have been identified in individuals with typical Klippel-Trenaunay syndrome [Revencu et al 2013a]. Mosaic variants in PIK3CA have been reported in KTS [Vahidnezhad et al 2016].


PHTS includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome.


Hereditary GVMs have a cobblestone appearance with a consistency harder than that of venous malformations. Histologically, glomuvenous malformations are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels [Brouillard et al 2002].

Deletion 5q14.3q15. One individual with a 3.1-Mb deletion of 5q14.3q15 including RASA1 and four other genes has been reported [Carr et al 2011]. Findings included multifocal CMs and severe developmental delay associated with MEF2C haploinsufficiency. In their review of the findings in four other individuals previously reported with deletions of both RASA1 and MEF2C, Carr et al [2011] determined that CMs had not been reported. The severe developmental delays are not thought to result from deletion of RASA1.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a RASA1-related disorder, the following evaluations are recommended:

  • Medical history and physical examination with a focus on symptoms and findings secondary to arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs)
  • Brain imaging –if not already performed- to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated prior to the development of symptoms [Revencu et al 2008]
  • Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with RASA1-related disorders have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
  • Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Capillary malformations (CMs). Referral to a dermatologist can be considered for evaluation of CMs that are of cosmetic concern and discussion of the risks and benefits of intervention.

AVMs/AVFs. The risks and benefits of intervention for AVMs and AVFs must be considered. Depending on the location and symptoms of AVMs/AVFs, a multi-disciplinary team including specialists in interventional radiology, neurosurgery, surgery, cardiology, and dermatology is recommended to determine appropriate approaches (e.g., embolization vs. surgery).

Cardiac overload. Referral to a cardiologist is indicated if cardiac overload is suspected.

Hemihyperplasia and/or leg length discrepancy. Referral to an orthopedist is recommended in individuals with hemihyperplasia and leg length discrepancy.

Lymphangiography to evaluate for lymphatic malformations may be considered. Compression stockings for those with evidence of lymphedema may be considered.


The clinician should have a low threshold to repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident over time.

Agents/Circumstances to Avoid

Although no agents/circumstances resulting in complications of RASA1-related disorders have been reported, a theoretic consideration is avoidance of routine use of anticoagulants unless indicated for treatment of a different medical condition.

Evaluation of Relatives at Risk

Clarification of the genetic status of at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes. In particular, at-risk infants are candidates for prompt diagnosis given the possible early presentation of neurologic complications from intracranial AVMs/AVFs [Revencu et al 2008].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

RASA1-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with a RASA1-related disorder have an affected parent.
  • A proband with a RASA1-related disorder may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is approximately 30% [Revencu et al 2008].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo RASA1 pathogenic variant.
  • If the RASA1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • The family history of an individual diagnosed with a RASA1-related disorder may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband has the RASA1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for a RASA1-related disorder because of the possibility of reduced penetrance in a parent.
  • If the RASA1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a RASA1-related disorder has a 50% chance of inheriting the RASA1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the RASA1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the RASA1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a RASA1-related disorder and preimplantation genetic diagnosis are possible options.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

RASA1-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for RASA1-Related Disorders (View All in OMIM)


Gene structure. RASA1 is 123 kb long and contains 25 coding exons. It produces a 4.3-kb mRNA product. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. The approximately 100 pathogenic variants reported to date are primarily nonsense, frameshift, or splice site variants [Eerola et al 2003, Hershkovitz et al 2008a, Hershkovitz et al 2008b, Revencu et al 2008, Wooderchak-Donahue et al 2012].

Although a few missense variants have also been identified within families, none has been confirmed as pathogenic using functional studies.

No recurrent variants have been identified.

Based on the currently identified pathogenic variants, haploinsufficiency is a suggested mechanism for the disease. Second hits have been proposed as a mechanism for development of the vascular lesions in the following two reports:

Normal gene product. RASA1 is a 1047-amino acid p120-RasGTPase-activating protein (p120-RasGAP). The N-terminal contains a Src homology region; the C-terminal contains a pleckstrin homology domain, protein kinase conserved region 2, and a RasGTPase-activating domain.

The protein RASA1 switches the active GTP-bound Ras to the inactive GDP-bound form. It is a negative regulator of the Ras/MAPK-signaling pathway which mediates cellular growth, differentiation, and proliferation from various protein kinases on cell surfaces.

Abnormal gene product. Germline heterozygous RASA1 pathogenic variants result in constitutive activation of Ras and resistance to GTPase-activating proteins GAPs.


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Suggested Reading

  • Brouillard P1, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. 2007;16 Spec No. 2:R140-9. [PubMed: 17670762]
  • Duffy K. Genetics and syndromes associated with vascular malformations. Pediatr Clin North Am. 2010;57:1111–20. [PubMed: 20888461]
  • Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, Young S, Plant P, Fülöp GT, Langa C, Morrell NW, Botella LM, Bernabeu C, Stevenson DA, Runo JR, Bayrak-Toydemir P. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93:530–7. [PMC free article: PMC3769931] [PubMed: 23972370]

Chapter Notes


We acknowledge Dr. Johannes Fredrik Grimmer for his insights.

Revision History

  • 6 October 2016 (bp) Comprehensive update posted live
  • 19 December 2013 (me) Comprehensive update posted live
  • 22 February 2011 (me) Review posted live
  • 6 December 2010 (pbt) Original submission
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