Submissions for variant NM_001370466.1(NOD2):c.2023C>T (p.Arg675Trp)

gnomAD frequency: 0.02936  dbSNP: rs2066844

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	RCV000203217	SCV000258186	uncertain significance	not specified	2015-04-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000365422	SCV000397254	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.
Illumina Laboratory Services, Illumina	RCV001781186	SCV000397255	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000203217	SCV000539927	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512783	SCV000636098	association	Blau syndrome; Regional enteritis	2025-02-03	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810832	SCV001157293	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000416493	SCV001499830	uncertain significance	Yao syndrome	2020-08-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262557	SCV002543734	uncertain significance	Autoinflammatory syndrome	2022-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001810832	SCV005325362	likely benign	not provided	2024-03-05	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
OMIM	RCV001781186	SCV000025133	risk factor	Inflammatory bowel disease 1	2002-07-01	no assertion criteria provided	literature only
OMIM	RCV000416493	SCV000494281	risk factor	Yao syndrome	2002-07-01	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV001535441	SCV001749347	not provided	Crohn disease		no assertion provided	phenotyping only	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.