Submissions for variant NM_001370466.1(NOD2):c.565+1G>A

gnomAD frequency: 0.00001  dbSNP: rs766614906

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498440	SCV000589782	likely pathogenic	not provided	2016-02-27	criteria provided, single submitter	clinical testing	The c.646+1G>A variant in the NOD2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 3. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.646+1G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.646+1G>A variant is a strong candidate for a pathogenic variant however the possibility it may be a rare benign variant cannot be excluded.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002261094	SCV002542742	uncertain significance	Autoinflammatory syndrome	2021-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV002527136	SCV003283115	uncertain significance	Blau syndrome; Regional enteritis	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the NOD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NOD2 cause disease. This variant is present in population databases (rs766614906, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NOD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 432100). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000498440	SCV004563481	uncertain significance	not provided	2023-10-27	criteria provided, single submitter	clinical testing	The NOD2 c.646+1G>A variant (rs766614906), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 432100). This variant is found in the general population with an overall allele frequency of 0.0018% (5/282892 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 3; however, loss-of-function variants are not an established mechanism of disease for Blau syndrome but have been associated with an increased risk for Crohn’s disease (Huang 2017). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Huang H et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 2017 Jul 13;547(7662):173-178. PMID: 28658209.