GRIN genes, function and associated disorders



Foundations, family groups, links to resources and more



Comprehensive information on variant interpretation



Filter and select a subset of variants for research



Information on the GRIN Registry and how to register










GRIN Genes and Neurodevelopmental Disorders

Information on GRIN1

History of GRIN1 Research

  • 2011
  • Hamdan et al.

    First Description of de novo Variants

    in individuals with intellectual disability
  • 2015
  • Ohba et al.

    Delineation of the Phenotype

  • 2016
  • Lemke et al.

    Delineation of the Phenotype

  • 2018
  • Fry et al.

    First Report of Cases with Brain Malformations

GRIN1-related Disorders

GRIN1-related disorder is characterized by mild-to-profound developmental delay / intellectual disability in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems. A subset of individuals shows a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. More details can be found on GeneReviews.

Clinical Information from the GRIN Registry (96 Individuals)


GRIN1 Phenotypes

Developmental Delay / Intellectual Disability

Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Seizures

Age at Seizure Onset


Movement Disorder

Further Phenotypes

Information on GRIN2A

History of GRIN2A Research

GRIN2A-related Disorder

GRIN2A-related disorder is characterized by either mild-to-profound developmental delay / intellectual disability in two thirds of affected individuals. Other common manifestations are speech disorders, epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems. More details can be found on GeneReviews.

Clinical Information from the GRIN Registry (158 Individuals)


GRIN2A Phenotypes

Developmental Delay / Intellectual Disability

Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Seizures

Age at Seizure Onset

Age at Seizure Offset


Movement Disorder

Further Phenotypes

Information on GRIN2B

History of GRIN2B Research

  • 2010
  • Endele et al.

    First Description of de novo Variants

    in individuals with intellectual disability
  • 2014
  • Lemke et al.

    Delineation of the Phenotype

  • 2017
  • Platzer et al.

    Delineation of the Phenotype

    first report of cases with brain malformations, first report on treatment with memantine in GoF cases
  • 2019
  • Soto et al.

    First Report on L-Serine Treatment

    in a Loss-of-Function case

GRIN2B-related Disorders

GRIN2B-related disorder is characterized by mild-to-profound developmental delay / intellectual disability in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems. A subset of individuals shows a malformation of cortical development consisting of extensive and diffuse bilateral polymicrogyria. More details can be found on GeneReviews.

Clinical Information from the GRIN Registry (162 Individuals)


GRIN2B Phenotypes

Developmental Delay / Intellectual Disability

Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Seizures

Age at Seizure Onset


Movement Disorder

Further Phenotypes

Information on GRIN2D

History of GRIN2D Research

  • 2016
  • Li et al.

    First Description of de novo Variants

    with epileptic encephalopythy, first report on treatment with memantine, ketamine and magnesium in GoF cases
  • 2019
  • XiangWei et al.

    Delineation of the Phenotype

GRIN2D-related Disorders

GRIN2D-related disorder is characterized by moderate-to-profound developmental delay / intellectual disability in all affected individuals. Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior problems.

Only few individuals have been reported in the GRIN Registry yet.

For Families







GRIN Genes and Related Disorders

If your family has received a diagnosis of GRIN-related disorders, you’ve probably never heard of it before. That’s okay. Your doctors probably haven’t either! But the GRIN Portal community is here to help.

This 6-minute “What are GRIN-related disorders?” video helps families learn about these disorders in plain language. You’ll learn:

• Scientific terms (such as genes, proteins, and variants/mutations) that will help you understand GRIN-related disorders
• What causes GRIN-related disorders
• How GRIN-related disorders are diagnosed
• The symptoms of GRIN-related disorders

Thank you to all contributors!

International

National

Italy

Germany

Spain

Brasil

...and many more! Please contact us if you would like your organization to be listed here.

Enter variant

Variant Information



Clinical Significance

Explanation

The following criteria were automatically annotated:


Evidence specifications: VS, very strong; S, strong; M, moderate; P, supporting


PVS1 - Null variant in a gene where loss of function is a known mechanism of disease. Very Strong evidence.

PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Strong - supporting evidence.

PS2 - De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Very strong - supporting evidence. For specifications see here.

PS3 - Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Strong - moderate evidence.

PS4 - The same variant has been previously identified in two or more/one unrelated affected individuals and has not been reported in gnomAD. Moderate - supporting evidence.

PM1 - Located in an “intolerant 3D microdomain” without benign variation. Right now only available for GRIN2B. Moderate - supporting evidence.

PM2 - Completely absent from all population databases (at least from gnomAD). Supporting evidence.

PM5 - Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Moderate - supporting evidence.

PM6 - Assumed de novo, but without confirmation of paternity and maternity. Very strong - supporting evidence. For specifications see here.

PP2 - Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Supporting evidence.

PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Supporting evidence.

Registry Information


Individuals with the same variant in the GRIN Registry


Abbreviations: DD/ID, Developmental Delay/Intellectual Disability; ASD, Autism Spectrum Disorder; MD, Movement Disorder; MCD, Malformation of Cortical Development; CVI, Cerebral Visual Impairment






Functional Summary


Overview The potential net effect of changes in NMDA receptor function assessed in vitro were categorized by the same numerical threshold used as supporting evidence for pathogenicity in ACMG criteria. These thresholds used the variability of functional measurements in variants observed in the general population to determine confidence intervals with which a patient-derived variant could be judged unlikely to occur by chance in the general population.

Likely Gain-of-Function (Supporting Pathogenic): Changes that increase receptor activity for one of the following parameters (without offsetting changes) of >3-fold decrease in glutamate or glycine EC50 value, >2-fold increase in Mg2+ IC50 value, >2-fold increase in the weighted tau deactivation (tauW), >2-fold increase in open probability, >3-fold increase in surface expression, all assays with appropriate biological replicates compared to values determined with the same assay on the same day for wild-type controls.

Likely Loss-of-Function (Supporting Pathogenic): Changes that decrease receptor activity for one of the following parameters (without offsetting changes) of >3-fold increase in glutamate or glycine EC50 value, >2-fold decrease in Mg2+ IC50 value, >2-fold decrease in deactivation tauW, >2-fold decrease in open probability, >3-fold decrease in surface expression, all assays with appropriate biological replicates compared to values determined with the same assay on the same day for wild-type controls.

Potential Gain-of-Function (Supporting Pathogenic): Changes in two or more parameters that increase receptor activity, including 1.5-3-fold decrease in glutamate or glycine EC50 value, 1.5-2-fold increase in Mg2+ IC50 value, 1.5-2-fold increase in deactivation tauW, 1.25-2-fold increase in open probability, or 2-3-fold increase in surface expression, all assays with appropriate biological replicates compared to values determined with the same assay on the same day for wild-type controls

Potential Loss-of-Function (Supporting Pathogenic): Changes in two or more parameters that decrease receptor activity, including 1.5-3-fold increase in glutamate or glycine EC50 value, 1.5-2-fold decrease in Mg2+ IC50 value, 1.5-2-fold decrease in deactivation tauW, 1.25-2-fold decrease in open probability, or 2-3-fold decrease in surface expression, all assays with appropriate biological replicates compared to values determined with the same assay on the same day for wild-type controls

Complex: Change to more than one parameter in excess of any threshold described above with opposing effects on receptor activity.

Insufficient Data: Currently there is insufficient data to support a pathogenic classification of this variant, although some parameters appear changed.

No Support for Pathogenicity: Currently the data do not support a pathogenic classification of this variant.


Abbreviations: DD/ID, Developmental Delay/Intellectual Disability; ASD, Autism Spectrum Disorder; MD, Movement Disorder; MCD, Malformation of Cortical Development; CVI, Cerebral Visual Impairment

Comparative Information

Compare the selected variant with other similar variants.

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Abbreviations: DD/ID, Developmental Delay / Intellectual Disability

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Filtered Subset

Selected variants are displayed in 2D (lolliplot) and 3D (protein structure).

Reference population missense variants (gnomAD)

The following transcripts were used: GRIN1: NM_007327.4, GRIN2A: NM_001134407.3, GRIN2B: NM_000834.4, GRIN2D: NM_000836.2

GRIN1 and GRIN2A Complex Structure

UniProt GRIN1: Q05586

GRIN1 and GRIN2A Complex Structure

UniProt GRIN2A: Q12879



UniProt GRIN2B: Q13224


UniProt GRIN2D: O15399

0 - no ID; 1 - mild ID; 2 - moderate ID; 3 - severe/profound ID


Functional data represent fold changes in receptor activity by gene variant compared to wild-type. Zero means no change from wild-type. Logarithmic scaling was used for the plot.



All data from the literature and:



Filtering is not yet available. A more comprehensive list will be updated soon.


Displayed Variants

Show Functional Data

How to enter the GRIN Registry

If you are from Europe, Asia, Africa or other

This chapter of the study is led by geneticist Dr. Johannes Lemke (University of Leipzig). Please fill out the online consent form and continue with the online clinical questionnaire; you can ask your doctor to help fill it out. Please keep your return code and return link to re-access your entry at a later time. The Leipzig team will contact CFERV to conduct functional studies for novel variants entered in the registry. In case we have questions on your entry, you may be contacted by an administrator. In case you have questions, please contact GRIN@medizin.uni-leipzig.de.

If you are from North or South America or Australia

please contact Jenifer Sargent (study coordinator) at: Jenifer.Sargent@cuanschutz.edu. This chapter of the study is led by neurologists Drs. Tim Benke and Kristen Park (University of Colorado) and Dr. Jennifer Bain ( Simons Foundation/Columbia University )

1. Email Jenifer Sargent your de-identified genetic testing results to make sure you qualify.
2. After we review your genetic testing results, Jenifer will send you a consent form; sign and return to her.
3. Jenifer will send you the clinical questionnaire. We are updating the questionnaire and want you to fill out the latest version, even if you've already done it before.
4. Fill out the questionnaire; you can ask your doctor to help fill it out.
5. Return the filled-out questionnaire to Jenifer; Jenifer will contact CFERV to conduct functional studies for novel variants.
6. In the near future, Jenifer will email you for yearly updates. If you haven't heard from us, then please contact us again.

Both chapters of the registry will be merged, and patients only need to be enrolled at Colorado or Leipzig. If you have already enrolled but have additional novel information, please get in contact and update your entry.


About

This is the alpha version of the GRIN Portal.

The GRIN Portal is a coalition of investigators seeking to aggregate and harmonize data generated to study GRIN-related disorders, and to make summary data interactively accessible for the wider scientific community, while providing educational resources for everyone. The goals of this project are:


- Providing information on GRIN-related disorders

- Supporting research on GRIN-related disorders

- Facilitating recruitment of individuals to the global GRIN registry

- Providing support in variant interpretation and classification

- Visualizing data from the global GRIN registry

- Linking researchers, clinicians and families


Teams and People

The current version of the GRIN Portal has been developed by an international team of researchers and clinicians:

Team Leaders

Johannes Lemke (Leipzig, Germany): General concept, clinical & genetic data

Tim Benke (Denver, US): Clinical & genetic data

Steve Traynelis (Atlanta, US): Molecular data

Dennis Lal (Cleveland, US): General concept, web development, bioinformatics, video production

Clinical & Genetic Data

Ilona Krey

Jenifer Sargent

Chiara Klöckner

Vincent Strehlow

Konrad Platzer

Molecular Data

Scott Myers

Hongjie Yuan

Animal Data

Amy Ramsey

Web Development

Chiara Klöckner

Marie Mcnee

Tobias Brünger

Eduardo Perez-Palma

Bioinformatics

Chiara Klöckner

Tobias Brünger

Eduardo Perez-Palma

Marie Mcnee

Patrick May

Video

Arthur Stefanski

Chiara Klöckner

Tobias Brünger

Marie Mcnee

Impressum

We object to any commercial use and disclosure of data.

Copyright and use: The authors grants you the right of use to make a private copy for personal purposes. However, you are not entitled to change and/or pass on the materials or publish them yourself. Upon request, you will receive free information about the personal data stored about you. To do so, please contact the administrator.

No liability: The contents of this web project have been carefully checked and created to the best of our knowledge. But for the information presented here is no claim to completeness, timeliness, quality and accuracy. No responsibility can be accepted for any damage caused by reliance on or use of the contents of this website.

Terms of Use

All data here are publicly for the benefit of the wider biomedical community. You can freely explore the data, and we encourage the use and publication of results generated from these data. However, we encourage you to contact us before embarking on analyses to check if your proposed analysis overlaps with work currently underway by our team. Further, we request that you actively acknowledge and give attribution to the GRIN Portal project, and link back to the relevant page, wherever possible. All users of our data agree to not attempt to reidentify participants. Our data set has been subjected to extensive quality control, but may be imperfect so errors may remain.

If you spot any results that seem impossible, or have suggestions for GRIN Portal improvements: Contact us that we can improve.

Data Generation

A full description of the methods used to aggregate and generated in this project will be provided shortly.