ClinVar Miner

Submissions for variant NM_022162.3(NOD2):c.1001G>A (p.Arg334Gln) (rs104895461)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482720 SCV000567303 pathogenic not provided 2015-08-16 criteria provided, single submitter clinical testing The R334Q variant in the NOD2 gene has been reported previously in multiple individuals diagnosed withBlau syndrome as well as expanded features including lymphadenopathy, interstitial lung disease, hepaticgranuloma, granulomatous arthritis, erythema nodosum, hypertension and recurrent fever (Rosé et al.,2015; Akil et al., 2010; Becker et al., 2007; Miceli-Richard et al., 2001). The R334Q substitution was notobserved in approximately 6500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The R334Qvariant is a semi-conservative amino acid substitution, which may impact secondary protein structure asthese residues differ in some properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function. Weinterpret R334Q as a pathogenic variant.
Invitae RCV000700396 SCV000829148 pathogenic Blau syndrome; Inflammatory bowel disease 1 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 334 of the NOD2 protein (p.Arg334Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant is a common cause of Blau syndrome. It has been shown to segregate with disease in several families, and has been observed in individuals with Blau syndrome, including a de novo occurrence (PMID: 11528384, 26606664, 24713464, 17393391, 20084402, 15554080). ClinVar contains an entry for this variant (Variation ID: 4694). Experimental studies have shown that this missense change disrupts NOD2 protein function (PMID: 25429073, 15044951, 25093298, 12626759). A different missense substitution at this codon, p.Arg334Trp, has been determined to be pathogenic (PMID: 11528384, 24713464, 22509093, 14522785, 17157607, 20199415, 17207093, 15459013, 15044951, 25416713). This supports that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004958 SCV000025134 pathogenic Blau syndrome 2001-09-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084070 SCV000116198 not provided Sarcoidosis, early-onset no assertion provided not provided

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