Welcome to the GRIN Portal

An interactive website for families, clinicians, and researchers dedicated to comprehending GRIN-related disorders












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
















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

  • 2021
  • Xu et al.

    First Report on memantine treatment in a gain-of-function case

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


GRIN1 Phenotypes

Developmental Delay / Intellectual Disability

Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Seizures

Age at seizure onset


Movement disorder

Cerebral visual impairment

Malformation of cortical development


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


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


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
  • 2022
  • Krey et al.

    First report on L-Serine treatment

    in cases with null variants

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


GRIN2B Phenotypes

Developmental Delay / Intellectual Disability

Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Seizures

Age at seizure onset


Movement Disorder

Further Phenotypes


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.

More details can be found on GeneReviews .

Clinical Information from the GRIN Registry


GRIN2D Phenotypes

Developmental Delay / Intellectual Disability

Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Seizures

Age at seizure onset


Movement Disorder

Further Phenotypes


What are GRIN-related Disorders?

Expert curated subtitles available in English, German, Danish, Greek, Russian, Spanish, Italian, Ukrainian, and Romanian.





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


Italy

Austria

Germany

Spain

Brasil

The Netherlands



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






Enter variant

e.g. c.301delCCC, c.1176dupA, c.393+1G>C


Only single amino acids exchanges resulting from SNV substitutions are considered: e.g p.Asp552Glu


Variant consequence

Variant Analysis lets you analyze single or multiple single-nucleotide variants (SNVs) in GRIN genes.

You may also download a report on the clinical significance of the variant (no medical advice).

Please select a variant on the left panel to see results.
Your input seems not correct, please verify that your input is correct. Please contact us if you think it's an error.
To the best of our knowledge there are no synonymous variants found so far that are associated with GRIN-related disorders. Thus, no variant specific results are displayed. Note that this may change in future versions of the GRIN-Portal. If you think that synonymous variants should get a detailed interface please contact us .
To the best of our knowledge there are no intronic variants found so far that are associated with GRIN-related disorders. Thus, no variant specific results are displayed. Note that this may change in future versions of the GRIN-Portal. If you think that intronic variants should get a detailed interface please contact us .

Analysis

Variant Information
Effect: Protein truncating
Registry Information

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


Abbreviations: DD/ID, Developmental Delay / Intellectual Disability

Analysis

Variant Information
Clinical Significance

Generate Report

Registry Information

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

All data obtained from CFERV . Please acknowledge CFERV if you use any of the functional data provided.

ND: Not determined.TSTM: Voltage current to small to measure. More specific parameter can be found at CFERV .



Functional data represent the fold change in receptor properties produced by the variant, with numbers greater than 1 indicating changes that enhance overall receptor function and could increase charge transfer, and numbers less than 1 indicating changes that diminish overall receptor function and could decrease the charge transfer. A value of 1 indicates function is similar to WT. Values greater than 10 in the radar plot are set to 10 and values less than 0.01 are set to 0.01 (see Table for actual values).

Disclaimer: The functional data on this website is provided for academic and research purposes only. It has not undergone clinical validation, and should not be used for medical advice, diagnosis, or treatment.

Show all functional data

ND: Not determined. TSTM: Voltage current to small to measure. More specific parameter can be found at CFERV .


Functional data represent the fold change in receptor properties produced by the variant, with numbers greater than 1 indicating changes that enhance overall receptor function and could increase charge transfer, and numbers less than 1 indicating changes that diminish overall receptor function and could decrease the charge transfer. A value of 1 indicates function is similar to WT. Values greater than 10 in the radar plot are set to 10 and values less than 0.01 are set to 0.01 (see Table for actual values).

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

In-silico predictions
EVE-score
Alpha-Missense
REVEL
GRIN-pathogenicity-score
GRIN functional prediction
Comparative Information
Compare the selected variant with other similar variants.


Abbreviations: DD/ID, Developmental Delay / Intellectual Disability


Requirements

The upload file must contain the following columns:
gene, c_pos, ref_c, alt_c, origin, phenotype.
gene = GRIN gene, c_pos = cDNA Position, ref_c = Reference, alt_c = Alternate

Please specify:
Origin
1: de novo confirmed
2: de novo assumed
3: other

Phenotype
1: Neurodevelopmental disorder (NDD) + Malformation of Cortical Development
2: NDD + Epilepsy or Cerebral Visual Impairment
3: unspecified NDD
4: other

Upload multiple GRIN variants
(.csv, .xlsx)

Input Example:
c_pos = cDNA Position, ref_c = Reference, alt_c = Alternate


Output


Filter GRIN Registry

Reset filters

Filtered Subset


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

Transcripts: GRIN1: NM_007327.4, GRIN2A: NM_001134407.3, GRIN2B: NM_000834.4, GRIN2D: NM_000836.2

UniProt GRIN1: Q05586

UniProt GRIN2A: Q12879



UniProt GRIN2B: Q13224


UniProt GRIN2D: O15399

Number of variants with phenotypic data per domain
Degree of the intellectual disability (ID)
Proportion of individuals with seizures

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. Fold changes below 0.02 are displayed as 0.02. Fold changes >50 are displayed as 50.



All data from the literature and:


Disclaimer: The functional data on this website is provided for academic and research purposes only. It has not undergone clinical validation, and should not be used for medical advice, diagnosis, or treatment.

Displayed Variants


Group 1
Reset filters
Group 2
Reset filters

2D protein scheme with selected variants (lolliplot)

3D protein model with selected variants

Subset 1
Subset 2
Combined subsets

Clinical information on selected variants

Phenotype Summary
Degree of intellectual disability
Seizures present
Age of seizure onset

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.

Info

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.

If you are from North or South America or Australia

1. Email grinresearch@cuanschutz.edu your de-identified genetic testing results to make sure you qualify (and any other questions too!).
2. After we review your genetic testing results, the research coordinator will send you a consent form; sign and return to them. This may take 1-2 weeks.
3. The coordinator 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 the coordinator; they will contact CFERV to conduct functional studies for novel variants. Functional analysis takes several months. Your clinician can contact us at grinresearch@cuanschutz.edu to review your results or to discuss medical management. We cannot discuss medical management with you directly.
6. In the near future, we will email you for yearly updates. If you haven't heard from us, then please contact us again. Thank you for participating!!!!


This is version 0.4 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

The project is overseen by Johannes Lemke (contact PI), Steve Traynelis (contact PI), Tim Benke and Dennis Lal. This GRIN Portal is an ongoing project and interested collaborators are invited to reach out to join the project. For more information about ongoing projects see here .
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

News
- v0.4 (01/08/2023) Update of clinical and functional dataset, literature references, family organizations, comparison of multiple subsets
- v0.3 (12/04/2022) Layout changes
- v0.2 (25/11/2021) Fixed minor bugs, updated clinical dataset, added variant report download and assessment of multiple variants, added pathogenic variant enriched regions and intolerant microdomains, added multiple family oganizations
- v0.1 (02/06/2021) Public release

Imprint
We object to any commercial use and disclosure of data.
Copyright and use: The authors grant 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. Upon request, you will receive free information about the personal data stored about you. To do so, please get in touch with 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. We cannot accept any responsibility for any damage caused by reliance on or use of the contents of this website.


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 our team's current work. 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 not to attempt to reidentify participants. Our data set has been subjected to extensive quality control but may be imperfect so that errors may remain.
If you spot any results that seem impossible or have suggestions for GRIN Portal improvements: contact us so that we can improve.


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