Submissions for variant NM_001370466.1(NOD2):c.1109C>T (p.Pro370Leu)

gnomAD frequency: 0.00021  dbSNP: rs150078153

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002528894	SCV000759524	likely benign	Blau syndrome; Regional enteritis	2023-09-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001784213	SCV001275004	uncertain significance	Inflammatory bowel disease 1	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001118317	SCV001276590	benign	Blau syndrome	2017-04-27	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811129	SCV002049691	uncertain significance	not provided	2022-01-14	criteria provided, single submitter	clinical testing	The NOD2 c.1190C>T, p.Pro397Leu variant (rs150078153) is reported in one individual with a systemic auto-inflammatory disease (Rusmini 2016), and one individual with Chron’s disease (Zouiten-Mekki 2005). However, neither patient had clear disease association. The variant is reported in the ClinVar database (Variant ID 531599) and is listed in the general population with an overall allele frequency of 0.02% (44/282,784 alleles) in the Genome Aggregation Database. The proline at codon 397 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.44). Due to limited information, the clinical significance of the p.Pro397Leu variant is uncertain at this time. References: Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7. PMID: 26386126. Zouiten-Mekki L et al. CARD15/NOD2 in a Tunisian population with Crohn's disease. Dig Dis Sci. 2005 Jan;50(1):130-5. PMID: 15712650.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263872	SCV002543019	uncertain significance	Autoinflammatory syndrome	2020-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905719	SCV004719321	uncertain significance	NOD2-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The NOD2 c.1190C>T variant is predicted to result in the amino acid substitution p.Pro397Leu. This variant has been reported in an individual with ulcerative colitis (Table S3, Horowitz et al. 2021. PubMed ID: 33692434) as well as, along with a truncating NPC1 variant, a patient with an atypical form of Crohn's disease with neurological deterioration present (Azab et al. 2022. PubMed ID: 35741735). This variant is reported in 0.027% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.