Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001854466 | SCV002248137 | likely pathogenic | Cryopyrin associated periodic syndrome | 2021-06-05 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with cryopyrin-associated periodic syndrome (CAPS) (PMID: 29163488, 26931528). This variant is also known as p.Ala352Thr. ClinVar contains an entry for this variant (Variation ID: 97912). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 354 of the NLRP3 protein (p.Ala354Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala354 amino acid residue in NLRP3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11687797, 30431487, 21109514, 29047407). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
| 3billion | RCV003152680 | SCV003842063 | likely pathogenic | Chronic infantile neurological, cutaneous and articular syndrome | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.52). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NLRP3 related disorder (ClinVar ID: VCV000097912 / PMID: 26931528). A different missense change at the same codon (p.Ala352Val) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004373). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Unité médicale des maladies autoinflammatoires, |
RCV000084170 | SCV000116301 | not provided | Familial cold autoinflammatory syndrome 1 | no assertion provided | not provided |