ClinVar Genomic variation as it relates to human health
NM_001370466.1(NOD2):c.2641G>C (p.Gly881Arg)
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.
Uncertain significance(5); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370466.1(NOD2):c.2641G>C (p.Gly881Arg)
Variation ID: 4692 Accession: VCV000004692.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q12.1 16: 50722629 (GRCh38) [ NCBI UCSC ] 16: 50756540 (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 Aug 1, 2016 Aug 4, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370466.1:c.2641G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357395.1:p.Gly881Arg missense NM_001293557.2:c.2641G>C NP_001280486.1:p.Gly881Arg missense NM_022162.3:c.2722G>C NP_071445.1:p.Gly908Arg missense NR_163434.1:n.2853G>C non-coding transcript variant NC_000016.10:g.50722629G>C NC_000016.9:g.50756540G>C NG_007508.1:g.30491G>C LRG_177:g.30491G>C LRG_177t1:c.2722G>C LRG_177p1:p.Gly908Arg Q9HC29:p.Gly908Arg - Protein change
- G908R, G881R
- Other names
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- Canonical SPDI
- NC_000016.10:50722628:G:C
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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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0.00459 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00459
1000 Genomes Project 30x 0.00593
Trans-Omics for Precision Medicine (TOPMed) 0.00941
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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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NOD2 | - | - |
GRCh38 GRCh37 |
944 | 1042 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Nov 11, 2015 | RCV000238745.12 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000268347.16 | |
risk factor (1) |
no assertion criteria provided
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Jul 1, 2002 | RCV000416490.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 22, 2023 | RCV000996266.35 | |
Benign (1) |
criteria provided, single submitter
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Feb 5, 2022 | RCV002260961.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 10, 2020 | RCV001781185.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 15, 2021 | RCV002054415.9 | |
association (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV002512782.9 |
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
Help
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
Help
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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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Blau syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140100.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Blau syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000397298.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inflammatory bowel disease 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000397297.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Dec 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inflammatory bowel disease 1
Affected status: yes
Allele origin:
germline
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Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984539.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Uncertain significance
(Apr 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Blau syndrome
Inflammatory bowel disease 1 Psoriatic arthritis, susceptibility to Yao syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495875.1
First in ClinVar: Apr 12, 2022 Last updated: Apr 12, 2022 |
Comment:
NOD2 NM_022162.2 exon 8 p.Gly908Arg (c.2722G>C):This variant has been reported in the literature in numerous individuals with a variety of phenotypes, most often in the … (more)
NOD2 NM_022162.2 exon 8 p.Gly908Arg (c.2722G>C):This variant has been reported in the literature in numerous individuals with a variety of phenotypes, most often in the context of immunological related presentations such as Crohn's disease or Irritable Bowel Disease (IBD) (Hugot 2001 PMID:11385576, Cuthbert 2002 PMID:11910337, Bonen 2003 PMID:12512038, Kabesch 2003 PMID:12704363, Girardelli 2018 PMID:29248579, Hui 2018 PMID:29321258, Gonzalez-Mancera 2020 PMID:32654169). In a large meta analysis study (PMID: 19713276), Individuals carrying this variant had an increased overall risk of Crohn's disease (OR = 2.6, 95% CI 2.2-2.9). However, this variant is present in several control individuals in the literature and is present in 1.4% (997/68018) of European alleles, including 5 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-50722629-G-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:4692) with classifications ranging from Variant of Uncertain Significance to Likely Benign as well as at least 1 entry as a Risk Allele. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies predict that this variant will impact the protein (Bonen 2003 PMID:12512038). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain but given the available data, the classification of this variant is likely most appropriate as a risk allele. (less)
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Uncertain significance
(Nov 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000297307.3
First in ClinVar: Aug 01, 2016 Last updated: Dec 24, 2022 |
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Likely benign
(Nov 22, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001159857.6
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
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association
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Regional enteritis
Blau syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000759521.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 908 of the NOD2 protein (p.Gly908Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 908 of the NOD2 protein (p.Gly908Arg). This variant is present in population databases (rs2066845, gnomAD 5%), including at least one homozygous and/or hemizygous individual. Numerous population-based case-control studies have shown that this variant confers an elevated risk of Crohn's disease (PMID: 21548950, 15024686, 18489434, 15190267, 15571588). In a large meta-analysis involving 75 case-control studies with 18,727 cases and 17,102 controls (PMID: 19713276), individuals carrying this variant had an increased overall risk of Crohn's disease (OR = 2.6, 95% CI 2.2-2.9). When all three NOD2 genotypes were combined (p.Arg702Trp, p.Gly908Arg, and p.Leu1007Profs*2), the odds ratios for Crohn's disease were 2.4 (95% CI, 2.0-2.8) for simple heterozygotes, 9.0 (95% CI 6.0-13.5) for compound heterozygotes, and 6.7 (95% CI 4.1-10.9) for homozygotes, compared with noncarriers. This variant is also known as G881R in the literature. ClinVar contains an entry for this variant (Variation ID: 4692). 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) performed at Invitae indicates that this missense variant is not expected to disrupt NOD2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change results in decreased NFkB activity and decreased response to lipopolysaccharide and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989). In summary, this is a frequently observed variant that is associated with approximately a 2.6-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele. (less)
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Benign
(Feb 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002542708.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Uncertain significance
(Mar 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001150915.25
First in ClinVar: Feb 03, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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risk factor
(Jul 01, 2002)
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no assertion criteria provided
Method: literature only
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INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025132.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to Hugot et al. (2001) identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene … (more)
Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to Hugot et al. (2001) identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene that was associated with an increased susceptibility to Crohn disease (IBD1; 266600). The allele frequency of this mutation was 0.11 among Crohn disease patients, 0.03 among ulcerative colitis (IBD1; 266600) patients, and 0.04 among unaffected controls. This mutation was designated GLY908ARG in the studies of Ogura et al. (2001) and Vermeire et al. (2002). Yao Syndrome, Susceptibility to Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, or Yao syndrome (YAOS; 617321), Yao et al. (2015) identified 1 patient who carried 3 NOD2 variants: G908R, R702W (605956.0003), and IVS8+158 (605956.0007). The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. (less)
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risk factor
(Jul 01, 2002)
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no assertion criteria provided
Method: literature only
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YAO SYNDROME, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000494280.2
First in ClinVar: Feb 04, 2017 Last updated: Dec 15, 2018 |
Comment on evidence:
Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to Hugot et al. (2001) identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene … (more)
Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to Hugot et al. (2001) identified a mutation leading to a gly881-to-arg (GLY881ARG) substitution in the NOD2 gene that was associated with an increased susceptibility to Crohn disease (IBD1; 266600). The allele frequency of this mutation was 0.11 among Crohn disease patients, 0.03 among ulcerative colitis (IBD1; 266600) patients, and 0.04 among unaffected controls. This mutation was designated GLY908ARG in the studies of Ogura et al. (2001) and Vermeire et al. (2002). Yao Syndrome, Susceptibility to Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, or Yao syndrome (YAOS; 617321), Yao et al. (2015) identified 1 patient who carried 3 NOD2 variants: G908R, R702W (605956.0003), and IVS8+158 (605956.0007). The authors noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease. (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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NOD2-associated autoinflammatory disease: a large cohort study. | Yao Q | Rheumatology (Oxford, England) | 2015 | PMID: 26070941 |
Distinct and overlapping genetic loci in Crohn's disease and ulcerative colitis: correlations with pathogenesis. | Waterman M | Inflammatory bowel diseases | 2011 | PMID: 21830272 |
Evaluation of 22 genetic variants with Crohn's disease risk in the Ashkenazi Jewish population: a case-control study. | Peter I | BMC medical genetics | 2011 | PMID: 21548950 |
Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis. | Yazdanyar S | Clinical chemistry | 2009 | PMID: 19713276 |
Variants of CARD15, TNFA and PTPN22 and susceptibility to Crohn's disease in the Czech population: high frequency of the CARD15 1007fs. | Hradsky O | Tissue antigens | 2008 | PMID: 18489434 |
Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. | Economou M | The American journal of gastroenterology | 2004 | PMID: 15571588 |
Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. | Li J | Human molecular genetics | 2004 | PMID: 15198989 |
NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe? | Arnott ID | Genes and immunity | 2004 | PMID: 15190267 |
Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families. | Tukel T | American journal of human genetics | 2004 | PMID: 15024686 |
The genetics of inflammatory bowel disease. | Bonen DK | Gastroenterology | 2003 | PMID: 12557156 |
Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. | Bonen DK | Gastroenterology | 2003 | PMID: 12512038 |
CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. | Vermeire S | American journal of human genetics | 2002 | PMID: 12019468 |
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. | Ogura Y | Nature | 2001 | PMID: 11385577 |
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. | Hugot JP | Nature | 2001 | PMID: 11385576 |
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Text-mined citations for rs2066845 ...
HelpRecord last updated Sep 01, 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.