Submissions for variant NM_001370466.1(NOD2):c.1459T>C (p.Tyr487His)

gnomAD frequency: 0.00001  dbSNP: rs540122692

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520892	SCV000617946	uncertain significance	not provided	2015-12-07	criteria provided, single submitter	clinical testing	The Y514H variant in the NOD2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Y514H 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 Y514H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (D512H, M513T, M513R) have been reported in the Human Gene Mutation Database in association with NOD2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret Y514H as a variant of uncertain significance.
Invitae	RCV002525125	SCV000944544	uncertain significance	Blau syndrome; Regional enteritis	2022-05-27	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 514 of the NOD2 protein (p.Tyr514His). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOD2 protein function. ClinVar contains an entry for this variant (Variation ID: 449632). This missense change has been observed in individual(s) with Yao syndrome (PMID: 30159790). This variant is present in population databases (rs540122692, gnomAD 0.03%).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000520892	SCV001477864	uncertain significance	not provided	2020-02-16	criteria provided, single submitter	clinical testing	The NOD2 c.1540T>C; p.Tyr514His variant (rs540122692) is described in the literature in one individual with suspected Yao syndrome (Yang 2018). The variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID: 449632) and in the general population with an overall allele frequency of 0.004% (11/250,384 alleles) in the Genome Aggregation Database. The tyrosine at codon 514 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Tyr514His variant is uncertain at this time. References: Yang et al. A Chinese case series of Yao syndrome and literature review. Clin Rheumatol. 2018 Dec;37(12):3449-3454.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002261098	SCV002542661	uncertain significance	Autoinflammatory syndrome	2021-11-17	criteria provided, single submitter	clinical testing