Submissions for variant NM_001370466.1(NOD2):c.2641G>T (p.Gly881Cys)

dbSNP: rs2066845

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000996267	SCV001150916	uncertain significance	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118603	SCV001276898	benign	Blau syndrome	2017-04-28	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001784530	SCV001278613	uncertain significance	Inflammatory bowel disease 1	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000996267	SCV001716267	uncertain significance	not provided	2022-03-22	criteria provided, single submitter	clinical testing	BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000996267	SCV002050139	uncertain significance	not provided	2021-03-16	criteria provided, single submitter	clinical testing	The NOD2 c.2722G>T; p.Gly908Cys variant (rs2066845) has not been reported in individuals with Blau syndrome but has been reported in an individual with orofacial granulomatosis (Mentzer 2016). This variant is reported in ClinVar (Variation ID: 808041). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.37% (38/10370 alleles) in the Genome Aggregation Database. The glycine at codon 908 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.385). However, given the lack of clinical and functional data, the significance of the p.Gly908Cys variant is uncertain at this time. References: Mentzer A et al. Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis. Inflamm Bowel Dis. 2016 Jul;22(7):1552-8.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549931	SCV002369491	benign	Blau syndrome; Regional enteritis	2023-11-19	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001118603	SCV002570265	uncertain significance	Blau syndrome	2022-04-09	criteria provided, single submitter	clinical testing	This NOD2 variant (rs2066845) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomAD: 38/10370 alleles; 0.37%; no homozgotes). This patient's ethnicity is reported to be Ashkenazi Jewish. This variant has been reported in ClinVar. While this variant has not been reported in individuals with Blau syndrome, it has been reported in an individual with orofacial granulomatosis. Three bioinformatic tools queried predict that this substitution would be damaging, and the glycine residue at this position is conserved across most mammalian species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. A NOD2 polymorphism affecting the same amino acid residue (p.Gly881Arg) is associated with susceptibility to Crohn disease and Yao syndrome. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.2641G>T to be uncertain at this time.