Submissions for variant NM_001370466.1(NOD2):c.59C>T (p.Ser20Leu)

gnomAD frequency: 0.00018  dbSNP: rs201586544

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001782788	SCV000397172	uncertain significance	Inflammatory bowel disease 1	2018-01-13	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.
Illumina Laboratory Services, Illumina	RCV000322676	SCV000397173	benign	Blau syndrome	2018-01-13	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.
Invitae	RCV002522852	SCV000636093	likely benign	Blau syndrome; Regional enteritis	2024-01-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001590949	SCV001472149	uncertain significance	not provided	2022-03-23	criteria provided, single submitter	clinical testing	The NOD2 c.140C>T; p.Ser47Leu variant (rs201586544), to our knowledge, is not reported in the literature in an individual with Blau syndrome, but has been reported in association with Crohn's disease (Chen 2018). The variant is described in the ClinVar database (Variation ID: 319424) and in the general population with an overall allele frequency of 0.02% (62/282550 alleles) in the Genome Aggregation Database. The amino acid at this position is moderately conserved and computational algorithms(PolyPhen-2, SIFT) predict this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain. REFERENCES Chen JS et al. Targeted Gene Sequencing in Children with Crohn's Disease and Their Parents: Implications for Missing Heritability. G3 (Bethesda). 2018 Aug 30;8(9):2881-2888.
GeneDx	RCV001590949	SCV001825680	uncertain significance	not provided	2021-02-10	criteria provided, single submitter	clinical testing	In a study of children with Crohn's disease, S47L reported with 0.24% allele frequency in cases and 0.12% allele frequency in controls (Chen et al., 2018); 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: 30166421)