. 2020 Jan;41(1):299-315.

doi: 10.1002/humu.23929. Epub 2019 Oct 26.

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Magdalena Koczkowska¹, Tom Callens¹, Yunjia Chen¹, Alicia Gomes¹, Alesha D Hicks¹, Angela Sharp¹, Eric Johns¹, Kim Armfield Uhas², Linlea Armstrong³, Katherine Armstrong Bosanko⁴, Dusica Babovic-Vuksanovic⁵, Laura Baker⁶, Donald G Basel⁷, Mario Bengala⁸, James T Bennett⁹, Chelsea Chambers¹⁰, Lola K Clarkson¹¹, Maurizio Clementi¹², Fanny M Cortés¹³, Mitch Cunningham¹⁴, M Daniela D'Agostino¹⁵, Martin B Delatycki¹⁶, Maria C Digilio¹⁷, Laura Dosa¹⁸, Silvia Esposito¹⁹, Stephanie Fox¹⁵, Mary-Louise Freckmann²⁰, Christine Fauth²¹, Teresa Giugliano²², Sandra Giustini²³, Allison Goetsch²⁴, Yael Goldberg²⁵, Robert S Greenwood²⁶, Cristin Griffis⁷, Karen W Gripp⁶, Punita Gupta²⁷, Eric Haan²⁸, Rachel K Hachen²⁹, Tamara L Haygarth³⁰, Concepción Hernández-Chico³¹, Katelyn Hodge³², Robert J Hopkin³³, Louanne Hudgins³⁴, Sandra Janssens³⁵, Kory Keller³⁶, Geraldine Kelly-Mancuso³³, Aaina Kochhar³⁷, Bruce R Korf¹, Andrea M Lewis³⁸, Jan Liebelt³⁹, Angie Lichty¹¹, Robert H Listernick²⁴, Michael J Lyons¹¹, Isabelle Maystadt⁴⁰, Mayra Martinez Ojeda⁴¹, Carey McDougall⁴², Lesley K McGregor³⁹, Daniela Melis⁴³, Nancy Mendelsohn⁴⁴, Malgorzata J M Nowaczyk⁴⁵, June Ortenberg¹⁵, Karin Panzer⁴⁶, John G Pappas⁴⁷, Mary Ella Pierpont⁴⁸, Giulio Piluso²², Valentina Pinna⁴⁹, Eniko K Pivnick⁵⁰, Dinel A Pond⁴⁴, Cynthia M Powell⁵¹, Caleb Rogers³⁶, Noa Ruhrman Shahar²⁵, S Lane Rutledge¹, Veronica Saletti¹⁹, Sarah A Sandaradura⁵², Claudia Santoro⁵³, Ulrich A Schatz²¹, Allison Schreiber⁵⁴, Daryl A Scott³⁸, Elizabeth A Sellars⁴, Ruth Sheffer⁵⁵, Elizabeth Siqveland⁴⁴, John M Slopis⁵⁶, Rosemarie Smith⁵⁷, Alberto Spalice⁵⁸, David W Stockton¹⁴, Haley Streff³⁸, Amy Theos⁵⁹, Gail E Tomlinson⁶⁰, Grace Tran⁶¹, Pamela L Trapane⁶², Eva Trevisson¹², Nicole J Ullrich⁶³, Jenneke Van den Ende⁶⁴, Samantha A Schrier Vergano⁶⁵, Stephanie E Wallace⁹, Michael F Wangler³⁸, David D Weaver³², Kaleb H Yohay⁶⁶, Elaine Zackai⁴², Jonathan Zonana³⁶, Vickie Zurcher⁵⁴, Kathleen B M Claes³⁵, Marica Eoli⁶⁷, Yolanda Martin³¹, Katharina Wimmer²¹, Alessandro De Luca⁴⁹, Eric Legius⁶⁸, Ludwine M Messiaen¹

Affiliations

¹ Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
² Children's Healthcare of Atlanta at Scottish Rite, Atlanta, Georgia.
³ Department of Medical Genetics, BC Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ Division of Clinical Genetics and Metabolism, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
⁵ Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota.
⁶ Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, Delaware.
⁷ Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
⁸ U.O.C Laboratorio di Genetica Medica, Dipartimento di Oncoematologia, Fondazione Policlinico di Tor Vergata, Rome, Italy.
⁹ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
¹⁰ Department of Neurology, University of Virginia Medical Center, Charlottesville, Virginia.
¹¹ Greenwood Genetic Center, Greenwood, South Carolina.
¹² Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.
¹³ Center for Rare Diseases, Clinica Las Condes, Santiago, Chile.
¹⁴ Division of Genetic, Genomic, and Metabolic Disorders, Detroit Medical Center, Children's Hospital of Michigan, Detroit, Michigan.
¹⁵ Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
¹⁶ Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
¹⁷ Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁸ SOC Genetica Medica, AOU Meyer, Florence, Italy.
¹⁹ Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
²⁰ Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
²¹ Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
²² Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
²³ Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
²⁴ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
²⁵ The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel.
²⁶ Division of Child Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
²⁷ Neurofibromatosis Diagnostic and Treatment Program, St. Joseph's Children's Hospital, Paterson, New Jersey.
²⁸ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²⁹ Neurofibromatosis Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
³⁰ Carolinas HealthCare System, Levine Children's Specialty Center, Charlotte, North Carolina.
³¹ Department of Genetics, Hospital Universitario Ramón y Cajal, Institute of Health Research (IRYCIS) and Center for Biomedical Research-Network of Rare Diseases (CIBERER), Madrid, Spain.
³² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
³³ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
³⁴ Division of Medical Genetics, Stanford University School of Medicine, Stanford, California.
³⁵ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
³⁶ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
³⁷ Department of Medical Genetics and Metabolism, Valley Children's Healthcare, Madera, California.
³⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
³⁹ The South Australian Clinical Genetics Service at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
⁴⁰ Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium.
⁴¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
⁴² Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
⁴³ Section of Pediatrics, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
⁴⁴ Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, Minnesota.
⁴⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
⁴⁶ University of Iowa Stead Family Children's Hospital, Iowa City, Iowa.
⁴⁷ Division of Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, New York.
⁴⁸ Department of Pediatrics and Opthalmology, University of Minnesota, Minneapolis, Minnesota.
⁴⁹ Molecular Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
⁵⁰ Department of Pediatrics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee.
⁵¹ Department of Genetics and Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
⁵² Division of Clinical Genetics, Department of Paediatrics and Child Health, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
⁵³ Specialistic and General Surgery Unit, Department of Woman and Child, Referral Centre of Neurofibromatosis, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
⁵⁴ Cleveland Clinic, Genomic Medicine Institute, Cleveland, Ohio.
⁵⁵ Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁵⁶ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵⁷ Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine.
⁵⁸ Child Neurology Division, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
⁵⁹ Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
⁶⁰ Division of Pediatric Hematology-Oncology, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.
⁶¹ Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁶² Division of Pediatric Genetics, Department of Pediatrics, University of Florida College of Medicine, Jacksonville, Florida.
⁶³ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
⁶⁴ Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
⁶⁵ Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia.
⁶⁶ Department of Neurology, New York University School of Medicine, Langone Medical Center, New York, New York.
⁶⁷ Division of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁶⁸ Department of Human Genetics, KU Leuven, Leuven, Belgium.

PMID: 31595648
PMCID: PMC6973139
DOI: 10.1002/humu.23929

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Magdalena Koczkowska et al. Hum Mutat. 2020 Jan.

. 2020 Jan;41(1):299-315.

doi: 10.1002/humu.23929. Epub 2019 Oct 26.

Authors

Affiliations

¹ Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.
² Children's Healthcare of Atlanta at Scottish Rite, Atlanta, Georgia.
³ Department of Medical Genetics, BC Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ Division of Clinical Genetics and Metabolism, Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
⁵ Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota.
⁶ Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, Delaware.
⁷ Children's Hospital of Wisconsin, Milwaukee, Wisconsin.
⁸ U.O.C Laboratorio di Genetica Medica, Dipartimento di Oncoematologia, Fondazione Policlinico di Tor Vergata, Rome, Italy.
⁹ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
¹⁰ Department of Neurology, University of Virginia Medical Center, Charlottesville, Virginia.
¹¹ Greenwood Genetic Center, Greenwood, South Carolina.
¹² Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy.
¹³ Center for Rare Diseases, Clinica Las Condes, Santiago, Chile.
¹⁴ Division of Genetic, Genomic, and Metabolic Disorders, Detroit Medical Center, Children's Hospital of Michigan, Detroit, Michigan.
¹⁵ Division of Medical Genetics, McGill University Health Centre, Montréal, Quebec, Canada.
¹⁶ Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
¹⁷ Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁸ SOC Genetica Medica, AOU Meyer, Florence, Italy.
¹⁹ Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
²⁰ Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
²¹ Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
²² Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
²³ Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.
²⁴ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
²⁵ The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel.
²⁶ Division of Child Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
²⁷ Neurofibromatosis Diagnostic and Treatment Program, St. Joseph's Children's Hospital, Paterson, New Jersey.
²⁸ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²⁹ Neurofibromatosis Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
³⁰ Carolinas HealthCare System, Levine Children's Specialty Center, Charlotte, North Carolina.
³¹ Department of Genetics, Hospital Universitario Ramón y Cajal, Institute of Health Research (IRYCIS) and Center for Biomedical Research-Network of Rare Diseases (CIBERER), Madrid, Spain.
³² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
³³ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
³⁴ Division of Medical Genetics, Stanford University School of Medicine, Stanford, California.
³⁵ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
³⁶ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon.
³⁷ Department of Medical Genetics and Metabolism, Valley Children's Healthcare, Madera, California.
³⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
³⁹ The South Australian Clinical Genetics Service at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
⁴⁰ Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium.
⁴¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
⁴² Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
⁴³ Section of Pediatrics, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
⁴⁴ Genomics Medicine Program, Children's Hospital Minnesota, Minneapolis, Minnesota.
⁴⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
⁴⁶ University of Iowa Stead Family Children's Hospital, Iowa City, Iowa.
⁴⁷ Division of Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, New York.
⁴⁸ Department of Pediatrics and Opthalmology, University of Minnesota, Minneapolis, Minnesota.
⁴⁹ Molecular Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
⁵⁰ Department of Pediatrics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee.
⁵¹ Department of Genetics and Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
⁵² Division of Clinical Genetics, Department of Paediatrics and Child Health, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
⁵³ Specialistic and General Surgery Unit, Department of Woman and Child, Referral Centre of Neurofibromatosis, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
⁵⁴ Cleveland Clinic, Genomic Medicine Institute, Cleveland, Ohio.
⁵⁵ Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁵⁶ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵⁷ Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine.
⁵⁸ Child Neurology Division, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
⁵⁹ Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.
⁶⁰ Division of Pediatric Hematology-Oncology, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.
⁶¹ Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁶² Division of Pediatric Genetics, Department of Pediatrics, University of Florida College of Medicine, Jacksonville, Florida.
⁶³ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
⁶⁴ Center for Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
⁶⁵ Division of Medical Genetics and Metabolism, Children's Hospital of the King's Daughters, Norfolk, Virginia.
⁶⁶ Department of Neurology, New York University School of Medicine, Langone Medical Center, New York, New York.
⁶⁷ Division of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
⁶⁸ Department of Human Genetics, KU Leuven, Leuven, Belgium.

PMID: 31595648
PMCID: PMC6973139
DOI: 10.1002/humu.23929

Abstract

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.

Keywords: NF1; genotype-phenotype correlation; p.Arg1276; p.Lys1423; p.Met1149.

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Conflict of interest statement

The authors declare that there are no conflict of interests.

Figures

**Figure 1**
Spectrum of six mutational hotspots at *NF1* codons 844‐848 (67/8,000), 992 (74/8,000), 1149 (34/8,000), 1276 (57/8,000), 1423 (52/8,000), and 1809 (99/8,000), affecting a total of 383/8,000 (4.8%) of unrelated probands in the University of Alabama at Birmingham (UAB) cohort, associated with mild (upper panel) or severe (lower panel) phenotypes. The figure was prepared using ProteinPaint application (Zhou et al., 2016). CSRD, cysteine‐serine rich domain; GAP, GTPase‐activating protein; GRD, GAP related domain; *NF1*, neurofibromatosis type 1; PH, pleckstrin homology‐like domain; Sec14, Sec14 homology‐like domain; Syn, syndecan binding domain; TBD, tubulin‐binding domain

**Figure 2**
Spectrum of pathogenic *NF1* missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423 in the studied cohort of 237 unrelated probands (a) and 44 relatives (b). Each number in the circle corresponds with the total number of individuals heterozygous for a specific variant. The figure was prepared using the ProteinPaint application (Zhou et al., 2016). GAP, GTPase‐activating protein; GRD, GAP related domain; *NF1*, neurofibromatosis type 1; TBD, tubulin‐binding domain

See this image and copyright information in PMC

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Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Affiliations

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous