ClinVar Genomic variation as it relates to human health
NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp)
Variation ID: 4696 Accession: VCV000004696.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q12.1 16: 50710911 (GRCh38) [ NCBI UCSC ] 16: 50744822 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 6, 2014 Apr 15, 2024 Oct 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370466.1:c.919C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357395.1:p.Arg307Trp missense NM_001293557.2:c.919C>T NP_001280486.1:p.Arg307Trp missense NM_022162.3:c.1000C>T NP_071445.1:p.Arg334Trp missense NR_163434.1:n.984C>T non-coding transcript variant NC_000016.10:g.50710911C>T NC_000016.9:g.50744822C>T NG_007508.1:g.18773C>T LRG_177:g.18773C>T LRG_177t1:c.1000C>T LRG_177p1:p.Arg334Trp Q9HC29:p.Arg334Trp - Protein change
- R334W, R307W
- Other names
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- Canonical SPDI
- NC_000016.10:50710910:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NOD2 | - | - |
GRCh38 GRCh37 |
941 | 1037 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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- | RCV000004960.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2022 | RCV001509512.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2023 | RCV002512785.9 |
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
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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
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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
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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. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Blau syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003924407.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
A Heterozygous Missense variant c.1000C>T in Exon 4 of the NOD2 gene that results in the amino acid substitution p.Arg334Trp was identified. The observed variantis … (more)
A Heterozygous Missense variant c.1000C>T in Exon 4 of the NOD2 gene that results in the amino acid substitution p.Arg334Trp was identified. The observed variantis novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 4696] The observed variation has previously been reported for Blau syndrome by Janarthanan, Mahesh, et al., 2019. Experimental studies have shown that this missense change affects NOD2 function by Tanabe, Tsuyoshi, et al., 2004. For these reasons this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Jul 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001716262.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP1_strong, PM2_supporting, PM5, PM6_strong, PS3, PS4
Number of individuals with the variant: 2
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Pathogenic
(Oct 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000759534.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the NOD2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the NOD2 protein (p.Arg334Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Blau syndrome (PMID: 11528384, 14522785, 15459013, 17157607, 17207093, 20199415, 22509093, 24713464, 25416713). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4696). 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 expected to disrupt NOD2 protein function. Experimental studies have shown that this missense change affects NOD2 function (PMID: 15044951, 15459013). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002545787.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Comment:
NOD2: PM2, PM5, PM6, PP1:Moderate, PP4, PS4:Supporting
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Blau syndrome
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002104289.2
First in ClinVar: Mar 19, 2022 Last updated: Apr 30, 2022 |
Sex: male
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Pathogenic
(Mar 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002574316.2
First in ClinVar: Sep 24, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a gain of function effect resulting in hyperactivation of the receptor (Parkhouse et al., 2014); Not observed at significant frequency in … (more)
Published functional studies demonstrate a gain of function effect resulting in hyperactivation of the receptor (Parkhouse et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32597225, 32881073, 32647028, 14522785, 17069729, 20199415, 22509093, 17916199, 28721627, 32707200, 17157607, 32346654, 31543536, 33923123, 34093558, 22377804, 24713464, 25429073, 31120540, 17372104, 30574935, 25416713, 11528384, 25093298) (less)
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Pathogenic
(Nov 01, 2008)
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no assertion criteria provided
Method: literature only
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BLAU SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025136.7
First in ClinVar: Apr 04, 2013 Last updated: Jun 15, 2018 |
Comment on evidence:
In affected members of a family with Blau syndrome (BLAUS; 186580), Miceli-Richard et al. (2001) found a 1000C-T transition in the NOD2 gene, resulting in … (more)
In affected members of a family with Blau syndrome (BLAUS; 186580), Miceli-Richard et al. (2001) found a 1000C-T transition in the NOD2 gene, resulting in an arg334-to-trp (R334W) substitution. In a 27-year-old Japanese man who had dermatitis and arthritis in infancy and later developed severe eye inflammation, persistent low-grade fever, and camptodactyly, Kanazawa et al. (2004) identified heterozygosity for the R334W mutation in the NOD2 gene. In 4 Japanese patients with early-onset sarcoidosis (Blau syndrome), including a patient originally reported by Sakurai et al. (1997) and the 27-year-old man previously studied by Kanazawa et al. (2004), Kanazawa et al. (2005) identified heterozygosity for the R334W mutation in the NOD2 gene. In a 63-year-old man with Blau syndrome, who exhibited severe camptodactyly and bilateral leg ulcerations, Dhondt et al. (2008) identified heterozygosity for the R334W mutation in the central nucleotide-binding oligomerization domain. (less)
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not provided
(-)
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no classification provided
Method: not provided
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Sarcoidosis, early-onset
Affected status: not provided
Allele origin:
not provided
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Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Accession: SCV000116197.1
First in ClinVar: Mar 06, 2014 Last updated: Mar 06, 2014
Comment:
also involved in OMIM 186580 and 266600
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation. | Matsuda T | Annals of the rheumatic diseases | 2020 | PMID: 32647028 |
Ophthalmological treatment of early-onset sarcoidosis/Blau syndrome in a Colombian child: A case report. | Marín-Noriega MA | American journal of ophthalmology case reports | 2020 | PMID: 32346654 |
Familial Blau syndrome:First molecularly confirmed report from India. | Janarthanan M | Indian journal of ophthalmology | 2019 | PMID: 30574935 |
Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. | Rosé CD | Rheumatology (Oxford, England) | 2015 | PMID: 25416713 |
Ultrasonographic assessment reveals detailed distribution of synovial inflammation in Blau syndrome. | Ikeda K | Arthritis research & therapy | 2014 | PMID: 24713464 |
Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. | Stoevesandt J | Pediatric dermatology | 2010 | PMID: 20199415 |
Leg ulcers: a new symptom of Blau syndrome? | Dhondt V | European journal of dermatology : EJD | 2008 | PMID: 18955195 |
Favourable effect of TNF-alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation. | Milman N | APMIS : acta pathologica, microbiologica, et immunologica Scandinavica | 2006 | PMID: 17207093 |
Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. | Kanazawa N | Blood | 2005 | PMID: 15459013 |
Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation. | Kanazawa N | The Journal of investigative dermatology | 2004 | PMID: 15086578 |
Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. | Tanabe T | The EMBO journal | 2004 | PMID: 15044951 |
CARD15 mutations in Blau syndrome. | Miceli-Richard C | Nature genetics | 2001 | PMID: 11528384 |
Preschool sarcoidosis mimicking juvenile rheumatoid arthritis: the significance of gallium scintigraphy and skin biopsy in the differential diagnosis. | Sakurai Y | Acta paediatrica Japonica : Overseas edition | 1997 | PMID: 9124059 |
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Text-mined citations for rs104895462 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.