Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002554608 | SCV001236041 | uncertain significance | Blau syndrome; Regional enteritis | 2023-07-29 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.His669Thrfs*94) in the NOD2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NOD2 cause disease. This premature translational stop signal has been observed in individual(s) with Crohn's disease (PMID: 30166421). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 863734). This variant is also known as P668fs. This variant is present in population databases (rs758485603, gnomAD 0.01%). |
| ARUP Laboratories, |
RCV001811641 | SCV001471051 | uncertain significance | not provided | 2019-12-24 | criteria provided, single submitter | clinical testing | The NOD2 c.2004delG; p.His669ThrfsTer94 variant (rs758485603), also known as P668fs, is reported in the literature in at least one individual affected with Crohn's disease (Chen 2018). This variant is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function variants are not an established mechanism of disease for Blau syndrome, but have been associated with an increased risk for Chron’s disease (Huang 2017). Thus, due to limited information, the clinical significance of the p.His669ThrfsTer94 variant is uncertain at this time. References: Chen 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. Huang H et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 2017 Jul 13;547(7662):173-178. |