ClinVar Miner

Submissions for variant NM_022162.3(NOD2):c.3019dup (p.Leu1007fs) (rs2066847)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000334899 SCV000397305 likely benign Crohn disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000389442 SCV000397306 likely benign Blau syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000525152 SCV000636103 risk factor Blau syndrome; Inflammatory bowel disease 1 2019-01-09 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. This variant is present in population databases (rs2066847, ExAC 2.0%), including multiple homozygous individuals. 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). 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.
OMIM RCV000004955 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

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