Submissions for variant NM_001370466.1(NOD2):c.2183C>T (p.Ala728Val)

gnomAD frequency: 0.00307  dbSNP: rs61747625

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001782824	SCV000397264	likely benign	Inflammatory bowel disease 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000341511	SCV000397265	likely benign	Blau syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513725	SCV000609697	likely benign	not provided	2017-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV002521040	SCV000636100	likely benign	Blau syndrome; Regional enteritis	2024-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513725	SCV001473737	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	The NOD2 c.2264C>T; p.Ala755Val variant (rs61747625) is reported in the literature in one individual with a periodic fever syndrome, in one individual with an autoinflammatory disorder, in several individuals with Crohn's disease or ulcerative colitis (Andreoletti 2017, Batlle-Maso 2020, Burillo-Sanz 2017, Hugot 2001, Lesage 2002), and three individuals with Blau syndrome (Parackova 2020, Rose 2015). The variant is also reported in ClinVar (Variation ID: 319462) and found in the non-Finnish European population with an allele frequency of 0.45% (579/128986 alleles including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.475). This variant has a population frequency incompatible with periodic fever disease and familial segregation study does not fully support its pathogenic role in Blau syndrome, although functional study indicates a gain-of-function of the p.Ala755Val variant (Parackova 2020). Due to conflicting information, the clinical significance of the p.Ala755Val variant is uncertain at this time.Andreoletti G et al. Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway. Sci Rep. 2017 Apr 19;7:46454. PMID: 28422189. Batlle-Maso L et al. Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing. Eur J Med Genet. 2020 May;63(5):103920. PMID: 32222431. Burillo-Sanz et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. PMID: 28814775. References: Andreoletti G et al. Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway. Sci Rep. 2017 Apr 19;7:46454. PMID: 28422189. Batlle-Maso L et al. Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing. Eur J Med Genet. 2020 May;63(5):103920. PMID: 32222431. Burillo-Sanz et al. Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. Sci Rep. 2017 Aug 16;7(1):8453. PMID: 28814775. Hugot et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):599-603. PMID: 11385576. Lesage S et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002 Apr;70(4):845-57. PMID: 11875755. Parackova Z et al. Mutual alteration of NOD2-associated Blau syndrome and IFN?R1 deficiency. J Clin Immunol. 2020 Jan;40(1):165-178. PMID: 31760574. Rose et al. Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. Rheumatology (Oxford). 2015 Jun;54(6):1008-16. PMID: 25416713.
GeneDx	RCV000513725	SCV001788319	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22056582, 12115249, 11385576, 28814775, 16485124, 20032092, 11875755, 16965521, 18640012, 28887115, 31760574, 28422189, 34440800, 34975878, 32222431, 25416713)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002056495	SCV002495872	uncertain significance	Blau syndrome; Psoriatic arthritis, susceptibility to; Yao syndrome; Inflammatory bowel disease 1	2021-08-09	criteria provided, single submitter	clinical testing	NOD2 NM_022162.2 exon 4 p.Ala755Val (c.2264C>T):This variant has been reported in the literature in several individuals with a variety of autoimmune conditions including Crohn's disease, Behcet's and Blau syndrome (also reported as p.Ala728Val-Hugot 2001 PMID:11385576, Rose 2015 PMID:25416713, Andreoletti 2017 PMID:28422189, Burillo-Sanz 2017 PMID:28814775, Batle-Maso 2020 PMID:32222431, Parakova 2020 PMID:31760574). This variant is present in 0.5% (357/68048) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-50712175-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from variant of uncertain significance to likely benign (Variation ID:319462). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000513725	SCV002497914	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	NOD2: BP4, BS1, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263017	SCV002543756	likely benign	Autoinflammatory syndrome	2020-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003920348	SCV004734495	likely benign	NOD2-related disorder	2020-06-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).