Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV002227059 | SCV001160553 | likely pathogenic | not provided | 2022-01-12 | criteria provided, single submitter | clinical testing | The NLRP3 c.908G>A; p.Gly303Asp variant (rs180177441) is reported in the medical literature in an individual affected with Cryopyrin-associated periodic syndrome (Han 2019). This variant is reported in ClinVar (Variation ID: 97978). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 303 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.717). Additionally, this amino acid is located in the extended Walker B motif in the NACHT domain, critical for ATP hydrolysis (MacDonald 2013). Based on available information, this variant is considered to be likely pathogenic. References: Han JH, et al. The First Case Series of Cryopyrin-Associated Periodic Syndrome in Korea. Allergy Asthma Immunol Res. 2019 Jul;11(4):583-588. PMID: 31172726 MacDonald JA, et al. Biochemical and structural aspects of the ATP-binding domain in inflammasome-forming human NLRP proteins. IUBMB Life. 2013 Oct;65(10):851-62. PMID: 24078393. |
| Labcorp Genetics |
RCV001857410 | SCV002230103 | pathogenic | Cryopyrin associated periodic syndrome | 2022-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 303 of the NLRP3 protein (p.Gly303Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cryopyrin-associated periodic syndrome (PMID: 21109514, 31172726; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as G301D. ClinVar contains an entry for this variant (Variation ID: 97978). 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 NLRP3 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Unité médicale des maladies autoinflammatoires, |
RCV000084239 | SCV000116375 | not provided | Familial cold autoinflammatory syndrome 1 | no assertion provided | not provided |