NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp) AND Blau syndrome

Germline classification:: Pathogenic (4 submissions)
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004960.21

Allele description [Variation Report for NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp)]

NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp)

Gene:

NOD2:nucleotide binding oligomerization domain containing 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q12.1

Genomic location:

Preferred name:

NM_001370466.1(NOD2):c.919C>T (p.Arg307Trp)

HGVS:

NC_000016.10:g.50710911C>T
NG_007508.1:g.18773C>T
NM_001293557.2:c.919C>T
NM_001370466.1:c.919C>TMANE SELECT
NM_022162.3:c.1000C>T
NP_001280486.1:p.Arg307Trp
NP_001357395.1:p.Arg307Trp
NP_071445.1:p.Arg334Trp
LRG_177t1:c.1000C>T
LRG_177:g.18773C>T
LRG_177p1:p.Arg334Trp
NC_000016.9:g.50744822C>T
NM_022162.1:c.1000C>T
NM_022162.2:c.1000C>T
NM_022162.3:c.1000C>T
NR_163434.1:n.984C>T
Q9HC29:p.Arg334Trp

Protein change:

R307W; ARG334TRP

Links:

UniProtKB: Q9HC29#VAR_012677; OMIM: 605956.0006; dbSNP: rs104895462

NCBI 1000 Genomes Browser:

rs104895462

Molecular consequence:

NM_001293557.2:c.919C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370466.1:c.919C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022162.3:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_163434.1:n.984C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Blau syndrome (BLAUS)
Synonyms:: Synovitis granulomatous with uveitis and cranial neuropathies; Arthrocutaneouveal granulomatosis; Granulomatosis, familial, Blau type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008523; MedGen: C5201146; Orphanet: 90340; OMIM: 186580

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025136	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2008)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 11528384, 9124059, 15086578, 15459013, 18955195
SCV000116197	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	no classification provided	not provided	unknown	not provided
SCV002104289	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (1) [See all records that cite this PMID]
SCV003924407	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30574935, 15044951, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CARD15 mutations in Blau syndrome.

Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Häfner R, Chamaillard M, Zouali H, Thomas G, Hugot JP.

Nat Genet. 2001 Sep;29(1):19-20.

PubMed [citation]

PMID:: 11528384

Preschool sarcoidosis mimicking juvenile rheumatoid arthritis: the significance of gallium scintigraphy and skin biopsy in the differential diagnosis.

Sakurai Y, Nakajima M, Kamisue S, Nishimura Y, Ueda T, Miyagawa S, Hara T, Yoshioka A.

Acta Paediatr Jpn. 1997 Feb;39(1):74-8.

PubMed [citation]

PMID:: 9124059

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000025136.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Unité médicale des maladies autoinflammatoires, CHRU Montpellier, SCV000116197.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002104289.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003924407.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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