ClinVar Genomic variation as it relates to human health
NM_201525.4(ADGRG1):c.112C>T (p.Arg38Trp)
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.
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(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_201525.4(ADGRG1):c.112C>T (p.Arg38Trp)
Variation ID: 5829 Accession: VCV000005829.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q21 16: 57651247 (GRCh38) [ NCBI UCSC ] 16: 57685159 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 4, 2016 Sep 16, 2024 Jul 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_201525.4:c.112C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_958933.1:p.Arg38Trp missense NM_001145770.3:c.112C>T NP_001139242.1:p.Arg38Trp missense NM_001145771.3:c.112C>T NP_001139243.1:p.Arg38Trp missense NM_001145772.3:c.112C>T NP_001139244.1:p.Arg38Trp missense NM_001145773.3:c.127C>T NP_001139245.1:p.Arg43Trp missense NM_001145774.3:c.112C>T NP_001139246.1:p.Arg38Trp missense NM_001290142.2:c.110+2C>T splice donor NM_001290143.2:c.-414C>T 5 prime UTR NM_001290144.2:c.-414C>T 5 prime UTR NM_001370428.1:c.112C>T NP_001357357.1:p.Arg38Trp missense NM_001370429.1:c.112C>T NP_001357358.1:p.Arg38Trp missense NM_001370430.1:c.112C>T NP_001357359.1:p.Arg38Trp missense NM_001370431.1:c.112C>T NP_001357360.1:p.Arg38Trp missense NM_001370432.1:c.112C>T NP_001357361.1:p.Arg38Trp missense NM_001370433.1:c.127C>T NP_001357362.1:p.Arg43Trp missense NM_001370434.1:c.112C>T NP_001357363.1:p.Arg38Trp missense NM_001370435.1:c.112C>T NP_001357364.1:p.Arg38Trp missense NM_001370436.1:c.112C>T NP_001357365.1:p.Arg38Trp missense NM_001370437.1:c.112C>T NP_001357366.1:p.Arg38Trp missense NM_001370438.1:c.112C>T NP_001357367.1:p.Arg38Trp missense NM_001370439.1:c.112C>T NP_001357368.1:p.Arg38Trp missense NM_001370440.1:c.112C>T NP_001357369.1:p.Arg38Trp missense NM_001370441.1:c.112C>T NP_001357370.1:p.Arg38Trp missense NM_001370442.1:c.65-109C>T intron variant NM_001370451.1:c.-414C>T 5 prime UTR NM_001370453.1:c.-414C>T 5 prime UTR NM_001370454.1:c.-414C>T 5 prime UTR NM_005682.5:c.112C>T NM_005682.7:c.112C>T NP_005673.3:p.Arg38Trp missense NM_201524.4:c.112C>T NP_958932.1:p.Arg38Trp missense NC_000016.10:g.57651247C>T NC_000016.9:g.57685159C>T NG_011643.1:g.36250C>T NG_160843.1:g.144C>T Q9Y653:p.Arg38Trp - Protein change
- R38W, R43W
- Other names
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- Canonical SPDI
- NC_000016.10:57651246:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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ADGRG1 | - | - |
GRCh38 GRCh37 |
942 | 970 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Jul 24, 2024 | RCV000006185.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001813956.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2023 | RCV003565380.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 15, 2022 | RCV004018573.1 |
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
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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
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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. |
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Pathogenic
(Dec 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004323840.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 38 of the ADGRG1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 38 of the ADGRG1 protein (p.Arg38Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with bilateral frontoparietal polymicrogyria (PMID: 15044805, 16240336). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADGRG1 protein function. Experimental studies have shown that this missense change affects ADGRG1 function (PMID: 21349848, 22238662). This variant disrupts the p.Arg38 amino acid residue in ADGRG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16240336, 17576745, 22238662, 23981349, 25922261). 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)
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Likely pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755624.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Uncertain significance
(Sep 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004859447.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.112C>T (p.R38W) alteration is located in exon 4 (coding exon 2) of the ADGRG1 gene. This alteration results from a C to T substitution … (more)
The c.112C>T (p.R38W) alteration is located in exon 4 (coding exon 2) of the ADGRG1 gene. This alteration results from a C to T substitution at nucleotide position 112, causing the arginine (R) at amino acid position 38 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Pathogenic
(Jul 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Bilateral frontoparietal polymicrogyria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005202854.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: ADGRG1 c.112C>T (p.Arg38Trp) results in a non-conservative amino acid change located in the PTX/LNS-Like (PLL) domain (IPR040679) of the encoded protein sequence. Four … (more)
Variant summary: ADGRG1 c.112C>T (p.Arg38Trp) results in a non-conservative amino acid change located in the PTX/LNS-Like (PLL) domain (IPR040679) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251474 control chromosomes. c.112C>T has been reported in the literature in multiple homozygous individuals affected with Polymicrogyria, Bilateral Frontoparietal (e.g. Piao_2004, Piao_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolished ligand binding ability in HEK293T cells (Luo_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22238662, 16240336, 15044805). ClinVar contains an entry for this variant (Variation ID: 5829). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Specific and direct modulation of the interaction between adhesion GPCR GPR56/ADGRG1 and tissue transglutaminase 2 using synthetic ligands. | Salzman GS | Scientific reports | 2020 | PMID: 33037308 |
Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains. | Salzman GS | Neuron | 2016 | PMID: 27657451 |
GPR56-Related Polymicrogyria: Clinicoradiologic Profile of 4 Patients. | Desai NA | Journal of child neurology | 2015 | PMID: 25922261 |
Mechanism for adhesion G protein-coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation. | Luo R | PloS one | 2014 | PMID: 24949629 |
Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria. | Fujii Y | Brain & development | 2014 | PMID: 23981349 |
Disease-associated mutations prevent GPR56-collagen III interaction. | Luo R | PloS one | 2012 | PMID: 22238662 |
G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. | Luo R | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21768377 |
Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. | Chiang NY | The Journal of biological chemistry | 2011 | PMID: 21349848 |
Biochemical characterization of genetic mutations of GPR56 in patients with bilateral frontoparietal polymicrogyria (BFPP). | Ke N | Biochemical and biophysical research communications | 2008 | PMID: 18042463 |
Disease-associated mutations affect GPR56 protein trafficking and cell surface expression. | Jin Z | Human molecular genetics | 2007 | PMID: 17576745 |
Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. | Piao X | Annals of neurology | 2005 | PMID: 16240336 |
G protein-coupled receptor-dependent development of human frontal cortex. | Piao X | Science (New York, N.Y.) | 2004 | PMID: 15044805 |
[Demonstration by Doppler echocardiography of multiple valvular involvement in carcinoid cardiopathy]. | Tribouilloy C | Archives des maladies du coeur et des vaisseaux | 1989 | PMID: 2494962 |
Epidemic malaria in the hyperendemic North Fly region of Western Province, Papua New Guinea. | Schuurkamp GJ | Papua and New Guinea medical journal | 1987 | PMID: 3303730 |
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Text-mined citations for rs121908462 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.