Submissions for variant NM_001370466.1(NOD2):c.1211C>T (p.Ser404Leu)

gnomAD frequency: 0.00103  dbSNP: rs104895431

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001781414	SCV000397219	uncertain significance	Inflammatory bowel disease 1	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514472	SCV001100920	likely benign	Blau syndrome; Regional enteritis	2024-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000954297	SCV001150910	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NOD2: BP4, BS1
Illumina Laboratory Services, Illumina	RCV000084081	SCV001278302	benign	Blau syndrome	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262677	SCV002543025	likely benign	Autoinflammatory syndrome	2020-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000954297	SCV003800374	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000084081	SCV000116210	not provided	Blau syndrome		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003974994	SCV004793750	uncertain significance	NOD2-related disorder	2023-12-22	no assertion criteria provided	clinical testing	The NOD2 c.1292C>T variant is predicted to result in the amino acid substitution p.Ser431Leu. This variant has been reported in individuals with inflammatory bowel disease or Crohn’s disease (Lesage et al. 2002. PubMed ID: 11875755; Rivas et al. 2011. PubMed ID: 21983784). Of note, this variant was also reported in patients with childhood onset inflammatory bowel disease (pIBD) (Andreoletti et al. 2017. PubMed ID: 28422189; Chen et al. 2018. PubMed ID: 30166421). This variant was also reported in the presence of additional NOD2 variants [c.2377G>A (p.Val793Met) and c.2798+158C>T] in at least two patients with NOD2-associated autoinflammatory disease (Yao et al. 2015. PubMed ID: 26070941). This variant was also reported in one individual in a study of patients with inherited retinal and optical nerve disorders (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926) and was identified in an individual with orofacial granulomatosis (Mentzer et al. 2016. PubMed ID: 27306066). Functional studies showed that this variant altered NOD2 protein localization and function (Rivas et al. 2011. PubMed ID: 21983784). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including two homozygous individuals and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/97826/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.