Submissions for variant NM_022162.3(NOD2):c.3019dup (p.Leu1007fs)

dbSNP: rs2066847

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000334899	SCV000397305	likely benign	Crohn disease	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000389442	SCV000397306	likely benign	Blau syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV002512781	SCV000636103	association	Blau syndrome; Regional enteritis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1007Profs*2) in the NOD2 gene. It is expected to result in an absent or disrupted protein product. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the NOD2 protein. This variant is present in population databases (rs2066847, gnomAD 3%), including at least one homozygous and/or hemizygous individual. Population-based case-control studies and family studies have shown that this variant confers an elevated risk of Crohn's disease (PMID: 21548950, 15024686, 18489434, 11425413, 11385576, 11385577, 11910337, 12019468, 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 = 3.8, 95% CI 3.4-4.3). 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 c.3020insC in the literature. ClinVar contains an entry for this variant (Variation ID: 4691). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this truncating variant conveys reduced production of cytokines upon bacterial exposure but is capable of inducing T-cell polarization (PMID: 18240302). This variant also demonstrated decreased NFkB activity and decreased response to lipopolysaccharide and peptidoglycan compared to wildtype protein (PMID: 12512038, 15198989), and impaired membrane association and signaling responses upon stimulation of synthetic immunoreactive peptides (PMID: 26500656, 22684479, 21335489). In summary, this is a frequently observed variant that is associated with approximately a 3.8-fold increased risk of Crohn's disease in population studies. Therefore, it has been classified as an Increased Risk Allele.
Mendelics	RCV000389442	SCV001140101	uncertain significance	Blau syndrome	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001701717	SCV002058052	likely benign	not provided	2023-10-26	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001701717	SCV002502239	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002260960	SCV002542721	uncertain significance	Autoinflammatory syndrome	2022-03-14	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224089	SCV003920298	uncertain significance	Blau syndrome; Yao syndrome; Inflammatory bowel disease 1	2022-10-18	criteria provided, single submitter	clinical testing	This variant has been reported in the literature as a risk allele and identified as heterozygous and homozygous in several individuals with Crohn's disease as well as control individuals(Hampe 2001 PMID:11425413, Ogura 2001 PMID:11385577, Bonen 2003 PMID:12512038, Girardelli 2018 PMID:29248579). This variant is present in 2.3% (3012/129102) of European alleles, including 92 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/16-50763778-G-GC). This variant is present in ClinVar, with at least 1 entry classfying this variant as a risk allele (Variation ID:4691). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies suggest a deleterious effect of this variant, reducing levels of NF-kB in response to bacterial lipopolysaccharide and peptidoglycan (Bonen 2003 PMID:12512038). However, further studies are needed to understand its impact. This variant is a duplication of 1 nucleotide and creates a premature stop codon 2 amino acids downstream from this location which results in an absent or abnormal protein. Of note, this variant occurs within the last two exons of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Further studies are needed to understand its impact. In summary, data on this variant support that this variant does not act as a true mendelian disorder variant, but may increase risk for Crohn's disease. Therefore, the clinical significance of this variant is classified as a risk allele.
OMIM	RCV001781184	SCV000025131	risk factor	Inflammatory bowel disease 1	2017-01-31	no assertion criteria provided	literature only
OMIM	RCV000416485	SCV000494279	risk factor	Yao syndrome	2017-01-31	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529584	SCV001743268	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701717	SCV001928554	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701717	SCV001973634	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001781184	SCV002577433	likely risk allele	Inflammatory bowel disease 1	2022-08-22	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV002468553	SCV002764630	established risk allele	Crohn’s Disease		no assertion criteria provided	research	The NOD2 c.3019dupC (p.Leu1007fs) variant was identified in population-based control studies and family studies, showing an elevated risk of Crohn’s Disease compared to the general population (PMID: 21548950, 15024686, 18489434, 11425413, 11385576, 11385577, 11910337, 12019468, 15190267, 15571588) (ClinVar entry by Invitae, Accession: SCV000636103.6). A large meta-analysis of 75 case-control studies suggests the odds ratio for Crohn’s disease to be 3.8 for carriers of the variant (95% CI 3.4-4.3) (ID: 19713276) (ClinVar entry by Invitae, Accession: SCV000636103.6). Schnitzler et al. characterized the NOD2 genotype of 1066 patients with Crohn’s Disease, identifying 54 individuals homozygous for the p.Leu1007fs variant, 153 heterozygotes, and 25 compound heterozygotes (freq: 13.4%). The variant was present at a significantly higher frequency in individuals with aggressive disease (15.6%) compared to those with mild disease (8.2%) (p = 2.6 x 10-5). Of the 54 individuals homozygous for the variant, 100% had ileal disease, compared to 82% of NOD2 wild-type carriers (p<0.0001). In combination with active smoking, homozygosity for this variant is associated with 100% risk for developing ileal stenosis requiring Crohn’s Disease-related surgical intervention (Schnitzler_2020_PMID: 32716958). The variant was also identified in dbSNP (ID: rs2066847) and ClinVar (classified as uncertain and likely benign in association with Yao Syndrome by Mendelics and Illumina, respectively, classified as likely benign and an increased risk allele in association with Crohn Disease by Illumina and Invitae, respectively, classified as likely benign in association with Inflammatory Bowel Disease 1; Blau Syndrome by ARUP Laboratories, and benign by University Medical Center Groningen) databases. The variant was identified in control databases in 4,298 of 282,762 chromosomes (115 homozygous) at a frequency of 1.52%, and was observed at the highest frequency in the Ashkenazi Jewish population in 355 of 10,364 chromosomes (freq: 3.43%) (Genome Aggregation Database March 6, 2019, v2.1.1). Functional studies have shown the variant causes reduced cytokine production upon exposure to bacteria, but is capable of inducing T-cell polarization (ID: 18240302), reduced NFkB activity, reduced response to lipopolysaccharide and peptidoglycan (PMID: 12512038, 15198989), and impaired membrane association and signaling response upon stimulation of synthetic immunoreactive peptides (PMID: 26500656, 22684479, 21335489) (ClinVar entry by Invitae, Accession: SCV000636103.6). The c.3019dupC variant occurs within 50 base pairs of the penultimate exon-exon junction. Variants in this region may escape non-sense mediated RNA decay, therefore the clinical significance of this variant cannot be determined with certainty at this time. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for Crohn’s Disease.