Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
ClinVar Genomic variation as it relates to human health
NM_001370466.1(NOD2):c.2023C>T (p.Arg675Trp)
Germline
Classification
Help
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.
(12)
Help
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.
Conflicting classifications of pathogenicity; association
Uncertain significance(3); Benign(2); Likely benign(3)
Uncertain significance(3); Benign(2); Likely benign(3)
12
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370466.1(NOD2):c.2023C>T (p.Arg675Trp)
Variation ID: 4693 Accession: VCV000004693.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q12.1 16: 50712015 (GRCh38) [ NCBI UCSC ] 16: 50745926 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 27, 2015 Sep 29, 2024 Mar 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370466.1:c.2023C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357395.1:p.Arg675Trp missense NM_001293557.2:c.2023C>T NP_001280486.1:p.Arg675Trp missense NM_022162.3:c.2104C>T NP_071445.1:p.Arg702Trp missense NR_163434.1:n.2088C>T non-coding transcript variant NC_000016.10:g.50712015C>T NC_000016.9:g.50745926C>T NG_007508.1:g.19877C>T LRG_177:g.19877C>T LRG_177t1:c.2104C>T Q9HC29:p.Arg702Trp - Protein change
- R702W, R675W
- Other names
- -
- Canonical SPDI
- NC_000016.10:50712014:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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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0.01438 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.01438
1000 Genomes Project 30x 0.01624
Exome Aggregation Consortium (ExAC) 0.02274
The Genome Aggregation Database (gnomAD), exomes 0.02605
The Genome Aggregation Database (gnomAD) 0.02936
Trans-Omics for Precision Medicine (TOPMed) 0.02987
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| NOD2 | - | - |
GRCh38 GRCh37 |
950 | 1048 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Mar 29, 2016 | RCV000203217.16 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000365422.13 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Aug 18, 2020 | RCV000416493.12 | |
| Likely benign (2) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001781186.12 | |
| not provided (1) |
no classification provided
|
- | RCV001535441.9 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 5, 2024 | RCV001810832.17 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 19, 2022 | RCV002262557.10 | |
| association (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV002512783.10 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Mar 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539927.1
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (less)
Method: Genome/Exome Filtration
|
|
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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inflammatory bowel disease 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000397255.3
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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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Blau syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000397254.3
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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Benign
(Nov 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157293.6
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
|
|
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association
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000636098.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 702 of the NOD2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 702 of the NOD2 protein (p.Arg702Trp). This variant is present in population databases (rs2066844, gnomAD 4%), 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: 11385576, 21548950, 18489434, 21274544, 15770725, 15024686, 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 = 2.2, 95% CI 2.0-2.5). 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 referred to as R675W and SNP8 in the literature. ClinVar contains an entry for this variant (Variation ID: 4693). 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, muramyl dipeptide, and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989, 18240302, 22684479). In summary, this is a frequently observed variant that is associated with approximately a 2.2-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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Uncertain significance
(Apr 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000258186.2
First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015 |
|
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Uncertain significance
(Aug 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Yao syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001499830.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Hematuria (present) , Arthritis (present) , Anemia (present) , Fever (present) , Abdominal pain (present) , Maturity onset diabetes mellitus in young (present)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Caucasians
Tissue: blood
|
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Uncertain significance
(Apr 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autoinflammatory syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002543734.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
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Likely benign
(Mar 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005325362.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
See Variant Classification Assertion Criteria.
|
|
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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
|
OMIM
Accession: SCV000025133.4
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 an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene … (more)
Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to Hugot et al. (2001) identified a mutation leading to an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene that was associated with increased susceptibility to Crohn disease (IBD1; 266600). The allele frequency of this mutation was 0.06 among Crohn disease patients, 0.01 among unaffected controls, and it was not present among ulcerative colitis patients. This mutation was designated ARG702TRP in the study of Vermeire et al. (2002). Yao Syndrome, Susceptibility to In 4 unrelated patients with multisystem autoinflammatory disease (YAOS; 617321), Yao et al. (2011) identified heterozygosity for the R702W mutation in the NOD2 gene. The patients also carried the known intronic variant IVS8+158 in NOD2 (605956.0007). Yao et al. (2011) stated that the clinical relevance of these mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. In a cohort of 22 patients with autoinflammatory disease that included the 7 patients previously studied by Yao et al. (2011), Yao et al. (2013) screened the NOD2 gene and identified heterozygosity for the R702W variant in 8 patients, all but 1 of whom also carried the IVS8+158 variant. Five of the 8 patients had varying degrees of gastrointestinal symptoms, but Yao et al. (2013) found no evidence of Crohn disease or ulcerative colitis after extensive evaluation. Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, Yao et al. (2015) identified 14 patients who were compound heterozygous for IVS8+158 and the R702W variant. 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
|
OMIM
Accession: SCV000494281.2
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 an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene … (more)
Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to Hugot et al. (2001) identified a mutation leading to an arg675-to-trp (ARG675TRP) substitution in the NOD2 gene that was associated with increased susceptibility to Crohn disease (IBD1; 266600). The allele frequency of this mutation was 0.06 among Crohn disease patients, 0.01 among unaffected controls, and it was not present among ulcerative colitis patients. This mutation was designated ARG702TRP in the study of Vermeire et al. (2002). Yao Syndrome, Susceptibility to In 4 unrelated patients with multisystem autoinflammatory disease (YAOS; 617321), Yao et al. (2011) identified heterozygosity for the R702W mutation in the NOD2 gene. The patients also carried the known intronic variant IVS8+158 in NOD2 (605956.0007). Yao et al. (2011) stated that the clinical relevance of these mutations remained to be determined, and that this disease might be genetically complex rather than mendelian. In a cohort of 22 patients with autoinflammatory disease that included the 7 patients previously studied by Yao et al. (2011), Yao et al. (2013) screened the NOD2 gene and identified heterozygosity for the R702W variant in 8 patients, all but 1 of whom also carried the IVS8+158 variant. Five of the 8 patients had varying degrees of gastrointestinal symptoms, but Yao et al. (2013) found no evidence of Crohn disease or ulcerative colitis after extensive evaluation. Among 54 patients with multisystem inflammatory disease and variants in the NOD2 gene, Yao et al. (2015) identified 14 patients who were compound heterozygous for IVS8+158 and the R702W variant. 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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not provided
(-)
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no classification provided
Method: phenotyping only
|
Crohn disease
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749347.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 6/29/2020 Invitae. GenomeConnect-Invitae Patient Insights Network … (more)
Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 6/29/2020 Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormal oral cavity morphology (present) , Asthma (present) , Bruising susceptibility (present) , Abnormal erythrocyte morphology (present) , Autoimmunity (present) , Immunodeficiency (present) , Abnormal … (more)
Abnormal oral cavity morphology (present) , Asthma (present) , Bruising susceptibility (present) , Abnormal erythrocyte morphology (present) , Autoimmunity (present) , Immunodeficiency (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Rheumatoid arthritis (present) , Abnormal intestine morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Precocious puberty (present) , Goiter (present) , Hyperthyroidism (present) , Abnormality of the bladder (present) , Depression (present) , Abnormal delivery (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-06-25
Testing laboratory interpretation: association
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Vertigo (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Abnormality of the neck (present) … (more)
Abnormality of vision (present) , Myopia (present) , Vertigo (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Asthma (present) , Decreased pulmonary function (present) , Abnormal pattern of respiration (present) , Autoimmunity (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Obesity (present) , Abnormal muscle physiology (present) , Abnormal curvature of the vertebral column (present) , Precocious puberty (present) , Hyperthyroidism (present) , Abnormality of the bladder (present) , Abnormality of the female genitalia (present) , Abnormality of the nervous system (present) , Seizure (present) , Depression (present) (less)
Indication for testing: Diagnostic|Family Testing
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-06-28
Testing laboratory interpretation: association
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Abnormality of the nose (present) , Thickened skin … (more)
Abnormality of vision (present) , Myopia (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Abnormality of the nose (present) , Thickened skin (present) , Hypercholesterolemia (present) , Asthma (present) , Autoimmunity (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormality of the liver (present) , Obesity (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormal limb bone morphology (present) , Hypogonadism (present) , Hyperthyroidism (present) , Type 2 diabetes mellitus (present) , Abnormal renal physiology (present) , Abnormality of urine homeostasis (present) , Anxiety (present) , Depression (present) , Pregnancy history (present) (less)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-06-29
Testing laboratory interpretation: association
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Comment:
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, 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.
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, 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 702 of the NOD2 protein (p.Arg702Trp). This variant is present in population databases (rs2066844, gnomAD 4%), 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: 11385576, 21548950, 18489434, 21274544, 15770725, 15024686, 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 = 2.2, 95% CI 2.0-2.5). 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 referred to as R675W and SNP8 in the literature. ClinVar contains an entry for this variant (Variation ID: 4693). 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, muramyl dipeptide, and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989, 18240302, 22684479). In summary, this is a frequently observed variant that is associated with approximately a 2.2-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele.
Comment:
See Variant Classification Assertion Criteria.
Comment:
Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 6/29/2020 Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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. |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
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, 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.
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, 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 702 of the NOD2 protein (p.Arg702Trp). This variant is present in population databases (rs2066844, gnomAD 4%), 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: 11385576, 21548950, 18489434, 21274544, 15770725, 15024686, 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 = 2.2, 95% CI 2.0-2.5). 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 referred to as R675W and SNP8 in the literature. ClinVar contains an entry for this variant (Variation ID: 4693). 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, muramyl dipeptide, and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989, 18240302, 22684479). In summary, this is a frequently observed variant that is associated with approximately a 2.2-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele.
Comment:
See Variant Classification Assertion Criteria.
Comment:
Variant reported in multiple Invitae PIN participants. Variant interpreted as an increased risk allele and reported most recently on 6/29/2020 Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NOD2-associated autoinflammatory disease: a large cohort study. | Yao Q | Rheumatology (Oxford, England) | 2015 | PMID: 26070941 |
| Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. | Yao Q | Journal of the American Academy of Dermatology | 2013 | PMID: 23102769 |
| The intermediate filament protein, vimentin, is a regulator of NOD2 activity. | Stevens C | Gut | 2013 | PMID: 22684479 |
| A new category of autoinflammatory disease associated with NOD2 gene mutations. | Yao Q | Arthritis research & therapy | 2011 | PMID: 21914217 |
| 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 |
| NOD2 exonic variations in Iranian Crohn's disease patients. | Naderi N | International journal of colorectal disease | 2011 | PMID: 21274544 |
| NOD2 gene polymorphism rs2066844 associates with need for combined liver-intestine transplantation in children with short-gut syndrome. | Ningappa M | The American journal of gastroenterology | 2011 | PMID: 20959815 |
| Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis. | Yazdanyar S | Clinical chemistry | 2009 | PMID: 19713276 |
| Frequency of three common mutations of CARD15/NOD2 gene in Iranian IBD patients. | Derakhshan F | Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology | 2008 | PMID: 18541930 |
| 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 |
| Monocyte-derived dendritic cells from Crohn patients show differential NOD2/CARD15-dependent immune responses to bacteria. | Salucci V | Inflammatory bowel diseases | 2008 | PMID: 18240302 |
| Analysis of the three common mutations in the CARD15 gene (R702W, G908R and 1007fs) in South African colored patients with inflammatory bowel disease. | Zaahl MG | Molecular and cellular probes | 2005 | PMID: 15967635 |
| Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. | Lakatos PL | World journal of gastroenterology | 2005 | PMID: 15770725 |
| 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 |
| 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 |
| 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 |
| CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. | Lesage S | American journal of human genetics | 2002 | PMID: 11875755 |
| 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 rs2066844 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 27, 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.