VCV000004691.40 - ClinVar

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

Germline

Classification

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.

(15)

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
Pathogenic(1); Uncertain significance(3); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 4691 Accession: VCV000004691.40

Type and length

Duplication, 1 bp

Location

Cytogenetic: 16q12.1 16: 50729867-50729868 (GRCh38) [ NCBI UCSC ] 16: 50763778-50763779 (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	Aug 22, 2016	Feb 28, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370466.1:c.2938dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001357395.1:p.Leu980fs
NM_001293557.2:c.2938dup	NP_001280486.1:p.Leu980fs
NM_022162.3:c.3019dup	NP_071445.1:p.Leu1007fs
NR_163434.1:n.3150dup
NC_000016.10:g.50729870dup
NC_000016.9:g.50763781dup
NG_007508.1:g.37732dup
LRG_177:g.37732dup
LRG_177t1:c.3019dup

... more HGVS ... less HGVS

Protein change

L980fs, L1007fs

Other names

Canonical SPDI

NC_000016.10:50729867:CCC:CCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00599 (CCCC)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 605956.0012 dbSNP: rs2066847 ClinGen: CA129325 OMIM: 605956.0001 VarSome

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
Gene	OMIM	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.
CYLD-AS1	-	-	-	GRCh38	-	88
NOD2		-	-	GRCh38 GRCh37	954	1052

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.
Blau syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 28, 2019	RCV000389442.16
Crohn disease	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000334899.13
Yao syndrome	risk factor (1)	no assertion criteria provided	Jan 31, 2017	RCV000416485.9
not specified	Benign (1)	no assertion criteria provided	-	RCV001529584.10
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Oct 26, 2023	RCV001701717.22
Inflammatory bowel disease 1	Likely risk allele; risk factor (2)	no assertion criteria provided	Aug 22, 2022	RCV001781184.10
Crohn’s Disease	Established risk allele (1)	no assertion criteria provided	-	RCV002468553.9
Autoinflammatory syndrome	Uncertain significance (1)	criteria provided, single submitter	Mar 14, 2022	RCV002260960.10
Blau syndrome Regional enteritis	association (1)	criteria provided, single submitter	Jan 31, 2024	RCV002512781.10
Blau syndrome Inflammatory bowel disease 1 Yao syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 18, 2022	RCV003224089.8

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.
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Blau syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140101.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502239.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (70): PubMed: 11385577 28422189 19397946 15002819 12673278 19641059 17301648 21335489 12512038 26167078 16010583 21951874 21745302 19185283 30166421 22543157 32597225 11910337 16669960 29867916 28750667 24047397 21565239 29248579 23173613 11425413 30553995 28658209 29321258 24345423 23128233 12704363 22440928 19748964 23633568 20713205 27373512 23709157 12650796 24586700 22344438 19103559 16416181 19184348 19184350 27306066 29178652 22275320 19349988 28008999 29446656 21548950 18942754 20332463 21983784 29795570 26042516 24597572 30167848 21994160 32716958 25365249 20047977 22684479 21460759 30552907 17489054 19713276 23615072 22939045 Number of individuals with the variant: 11 Secondary finding: no
Uncertain significance (Mar 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002542721.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Likely benign (Oct 26, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002058052.6 First in ClinVar: Jan 15, 2022 Last updated: Feb 20, 2024
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Blau Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000397306.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Crohn Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000397305.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Oct 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Blau syndrome Yao syndrome Inflammatory bowel disease 1 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920298.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: 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 … (more) 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. (less)
association (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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: SCV000636103.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (18) PubMed: 28492532‚ 21548950‚ 15024686‚ 18489434‚ 11425413‚ 11385576‚ 11385577‚ 11910337‚ 12019468‚ 15190267‚ 15571588‚ 19713276‚ 18240302‚ 12512038‚ 15198989‚ 26500656‚ 22684479‚ 21335489 Comment: This sequence change creates a premature translational stop signal (p.Leu1007Profs2) in the NOD2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu1007Profs2) 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. (less)
risk factor (Jan 31, 2017)	no assertion criteria provided Method: literature only	INFLAMMATORY BOWEL DISEASE 1 (CROHN DISEASE), SUSCEPTIBILITY TO Affected status: not provided Allele origin: not provided	OMIM Accession: SCV000025131.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016
risk factor (Jan 31, 2017)	no assertion criteria provided Method: literature only	YAO SYNDROME, SUSCEPTIBILITY TO Affected status: not provided Allele origin: not provided	OMIM Accession: SCV000494279.1 First in ClinVar: Feb 04, 2017 Last updated: Feb 04, 2017
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973634.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743268.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928554.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Likely risk allele (Aug 22, 2022)	no assertion criteria provided Method: clinical testing	Inflammatory bowel disease 1 Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV002577433.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022
Established risk allele (-)	no assertion criteria provided Method: research	Crohn’s Disease Affected status: unknown Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV002764630.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: 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 … (more) 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. (less)
click to load more click to collapse

Comment:

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.

Comment:

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.

Comment:

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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery.	Schnitzler F	PloS one	2020	PMID: 32716958
Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis.	Córdova-Fletes C	Autoimmunity	2020	PMID: 32597225
DNA variants in Helicobacter pylori infected patients with chronic gastritis, dysplasia and gastric cancer.	Hnatyszyn A	Advances in medical sciences	2019	PMID: 30553995
Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: The effect of NOD2/CARD15 mutations in a Tunisian population.	Touihri M	Human immunology	2019	PMID: 30552907
Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease.	Schiff ER	Human genetics	2018	PMID: 30167848
Targeted Gene Sequencing in Children with Crohn's Disease and Their Parents: Implications for Missing Heritability.	Chen JS	G3 (Bethesda, Md.)	2018	PMID: 30166421
Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond.	de Valles-Ibáñez G	Frontiers in immunology	2018	PMID: 29867916
Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.	Rivas MA	PLoS genetics	2018	PMID: 29795570
Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.	Pernat Drobež C	Genetic testing and molecular biomarkers	2018	PMID: 29446656
Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.	Hui KY	Science translational medicine	2018	PMID: 29321258
Genetic profile of patients with early onset inflammatory bowel disease.	Girardelli M	Gene	2018	PMID: 29248579
Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM).	Modi BP	Molecular genetics & genomic medicine	2017	PMID: 29178652
Co-existence of Blau syndrome and NAID? Diagnostic challenges associated with presence of multiple pathogenic variants in NOD2 gene: a case report.	Dziedzic M	Pediatric rheumatology online journal	2017	PMID: 28750667
Fine-mapping inflammatory bowel disease loci to single-variant resolution.	Huang H	Nature	2017	PMID: 28658209
Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway.	Andreoletti G	Scientific reports	2017	PMID: 28422189
Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population.	Ostrowski J	Scientific reports	2016	PMID: 28008999
Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families.	Levine AP	Gastroenterology	2016	PMID: 27373512
Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis.	Mentzer A	Inflammatory bowel diseases	2016	PMID: 27306066
Dysfunctional Crohn's Disease-Associated NOD2 Polymorphisms Cannot be Reliably Predicted on the Basis of RIPK2 Binding or Membrane Association.	Parkhouse R	Frontiers in immunology	2015	PMID: 26500656
NOD2/CARD15 gene mutations in North Algerian patients with inflammatory bowel disease.	Boukercha A	World journal of gastroenterology	2015	PMID: 26167078
NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis.	Salkic NN	Bosnian journal of basic medical sciences	2015	PMID: 26042516
The NOD2 p.Leu1007fsX1008 mutation (rs2066847) is a stronger predictor of the clinical course of Crohn's disease than the FOXO3A intron variant rs12212067.	Schnitzler F	PloS one	2014	PMID: 25365249
Two patients with intestinal failure requiring home parenteral nutrition, a NOD2 mutation and tuberculous lymphadenitis.	Schäffler H	BMC gastroenterology	2014	PMID: 24597572
NOD2 polymorphisms associated with cancer risk: a meta-analysis.	Liu J	PloS one	2014	PMID: 24586700
NOD2/CARD15 single nucleotide polymorphism 13 (3020insC) is associated with risk of sepsis and single nucleotide polymorphism 8 (2104C>T) with herpes viruses reactivation in patients after allogeneic hematopoietic stem cell transplantation.	Jaskula E	Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation	2014	PMID: 24345423
Card15 mutations and gastric cancer in a Portuguese population.	Freire P	Scandinavian journal of gastroenterology	2013	PMID: 24047397
NOD2 mutations affect muramyl dipeptide stimulation of human B lymphocytes and interact with other IBD-associated genes.	Lin Z	Digestive diseases and sciences	2013	PMID: 23709157
Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease.	Kirino Y	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23633568
Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.	Zhang W	Genes and immunity	2013	PMID: 23615072
Nucleotide oligomerization domain 2 polymorphisms in patients with intestinal failure.	Guerra JF	Journal of gastroenterology and hepatology	2013	PMID: 23173613
The intermediate filament protein, vimentin, is a regulator of NOD2 activity.	Stevens C	Gut	2013	PMID: 22684479
Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes.	Christodoulou K	Gut	2013	PMID: 22543157
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.	Jostins L	Nature	2012	PMID: 23128233
Prioritizing genetic variants for causality on the basis of preferential linkage disequilibrium.	Zhu Q	American journal of human genetics	2012	PMID: 22939045
Perianal Crohn's disease: predictive factors and genotype-phenotype correlations.	Kanaan Z	Digestive surgery	2012	PMID: 22440928
A systematic survey of loss-of-function variants in human protein-coding genes.	MacArthur DG	Science (New York, N.Y.)	2012	PMID: 22344438
Pattern recognition receptor and autophagy gene variants are associated with development of antimicrobial antibodies in Crohn's disease.	Murdoch TB	Inflammatory bowel diseases	2012	PMID: 22275320
Dominant disease-causing effect of NOD2 mutations in a family with all family members affected by Crohn's disease.	Schnitzler F	Inflammatory bowel diseases	2012	PMID: 21994160
NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis.	Bruns T	Liver international : official journal of the International Association for the Study of the Liver	2012	PMID: 21745302
Importance of NOD2/CARD15 gene variants for susceptibility to and outcome of sepsis in Turkish children.	Tekin D	Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies	2012	PMID: 21460759
Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.	Rivas MA	Nature genetics	2011	PMID: 21983784
Homozygous carrier of the NOD2 1007fs frame-shift mutation presenting with refractory community-acquired spontaneous bacterial peritonitis and developing fatal pulmonary mucormycosis: A case report.	Bruns T	Hepatology research : the official journal of the Japan Society of Hepatology	2011	PMID: 21951874
Association between NOD2/CARD15 polymorphisms and coronary artery disease: a case-control study.	Galluzzo S	Human immunology	2011	PMID: 21565239
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
Genome-wide expression profiling identifies an impairment of negative feedback signals in the Crohn's disease-associated NOD2 variant L1007fsinsC.	Billmann-Born S	Journal of immunology (Baltimore, Md. : 1950)	2011	PMID: 21335489
NOD2 mutations predict the risk for surgery in pediatric-onset Crohn's disease.	Lacher M	Journal of pediatric surgery	2010	PMID: 20713205
TLR4 and NOD2/CARD15 genetic polymorphisms and their possible role in gastric carcinogenesis.	Rigoli L	Anticancer research	2010	PMID: 20332463
Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph Consortium.	Skibola CF	American journal of epidemiology	2010	PMID: 20047977
Low prevalence of NOD2 SNPs in Behçet's disease suggests protective association in Caucasians.	Kappen JH	Rheumatology (Oxford, England)	2009	PMID: 19748964
Genotyping for NOD2 genetic variants and crohn disease: a metaanalysis.	Yazdanyar S	Clinical chemistry	2009	PMID: 19713276
First description of NOD2 variant associated with defective neutrophil responses in a woman with granulomatous mastitis related to corynebacteria.	Bercot B	Journal of clinical microbiology	2009	PMID: 19641059
NOD2/CARD15 polymorphisms impair innate immunity and increase susceptibility to gastric cancer in an Italian population.	Angeletti S	Human immunology	2009	PMID: 19397946
A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1.	Noguchi E	Nature immunology	2009	PMID: 19349988
Searching for genotype-phenotype structure: using hierarchical log-linear models in Crohn disease.	Chapman JM	American journal of human genetics	2009	PMID: 19185283
3020insC insertion in NOD2/CARD15 gene, a prevalent variant associated with anti-Saccharomyces cerevisiae antibodies and ileal location of Crohn's disease in Tunisian population.	Marrakchi R	Inflammation research : official journal of the European Histamine Research Society ... [et al.]	2009	PMID: 19184350
Interleukin 10 promoter region polymorphisms in inflammatory bowel disease in Tunisian population.	Marrakchi R	Inflammation research : official journal of the European Histamine Research Society ... [et al.]	2009	PMID: 19184348
[Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients].	Magyari L	Orvosi hetilap	2009	PMID: 19103559
Immune response and gene polymorphism profiles in Crohn's disease and ulcerative colitis.	Queiroz DM	Inflammatory bowel diseases	2009	PMID: 18942754
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
CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of European studies.	van der Linde K	European journal of gastroenterology & hepatology	2007	PMID: 17489054
Association of NOD2/CARD15 mutations on Crohn's disease phenotype in an Italian population.	Bianchi V	European journal of gastroenterology & hepatology	2007	PMID: 17301648
Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease.	D'Incà R	Alimentary pharmacology & therapeutics	2006	PMID: 16669960
Gastroduodenal Crohn's disease is associated with NOD2/CARD15 gene polymorphisms, particularly L1007P homozygosity.	Mardini HE	Digestive diseases and sciences	2005	PMID: 16416181
Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients.	Braat H	Journal of molecular medicine (Berlin, Germany)	2005	PMID: 16010583
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
NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn's disease patients: evidence for genetic heterogeneity within Europe?	Arnott ID	Genes and immunity	2004	PMID: 15190267
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
Frequency of NOD2/CARD15 variants in both sporadic and familial cases of Crohn's disease across Italy. An Italian Group for Inflammatory Bowel Disease Study.	Annese V	Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver	2004	PMID: 15002819
Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations.	Kabesch M	The Journal of allergy and clinical immunology	2003	PMID: 12704363
Association of NOD2 with Crohn's disease in a homogenous Irish population.	Bairead E	European journal of human genetics : EJHG	2003	PMID: 12673278
Card15 and Crohn's disease: healthy homozygous carriers of the 3020insC frameshift mutation.	Linde Kv	The American journal of gastroenterology	2003	PMID: 12650796
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
The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.	Cuthbert AP	Gastroenterology	2002	PMID: 11910337
Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.	Hampe J	Lancet (London, England)	2001	PMID: 11425413
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.	Ogura Y	Nature	2001	PMID: 11385577
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.	Hugot JP	Nature	2001	PMID: 11385576
click to load more click to collapse

Text-mined citations for rs2066847 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2066847 ...