Submissions for variant NM_001370466.1(NOD2):c.2641G>C (p.Gly881Arg)

dbSNP: rs2066845

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238745	SCV000297307	uncertain significance	not specified	2015-11-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001781185	SCV000397297	likely benign	Inflammatory bowel disease 1	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000268347	SCV000397298	likely benign	Blau syndrome	2017-04-27	criteria provided, single submitter	clinical testing	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.
Invitae	RCV002512782	SCV000759521	association	Blau syndrome; Regional enteritis	2024-01-29	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000268347	SCV001140100	uncertain significance	Blau syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000996266	SCV001150915	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000996266	SCV001159857	likely benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001781185	SCV001984539	uncertain significance	Inflammatory bowel disease 1	2020-12-10	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002054415	SCV002495875	uncertain significance	Blau syndrome; Psoriatic arthritis, susceptibility to; Yao syndrome; Inflammatory bowel disease 1	2021-04-15	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002260961	SCV002542708	benign	Autoinflammatory syndrome	2022-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV001781185	SCV000025132	risk factor	Inflammatory bowel disease 1	2002-07-01	no assertion criteria provided	literature only
OMIM	RCV000416490	SCV000494280	risk factor	Yao syndrome	2002-07-01	no assertion criteria provided	literature only