Submissions for variant NM_144687.4(NLRP12):c.857C>T (p.Pro286Leu)

gnomAD frequency: 0.00024  dbSNP: rs201940393

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000645639	SCV000767389	uncertain significance	Familial cold autoinflammatory syndrome 2	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 286 of the NLRP12 protein (p.Pro286Leu). This variant is present in population databases (rs201940393, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. ClinVar contains an entry for this variant (Variation ID: 536927). 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 NLRP12 protein function with a positive predictive value of 80%. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000645639	SCV001468387	uncertain significance	Familial cold autoinflammatory syndrome 2	2021-03-30	criteria provided, single submitter	clinical testing	NLRP12 NM_144687.3 exon3 p.Pro286Leu (c.857C>T): This variant has not been reported in the literature but is present in 0.04% (16/35418) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-54314056-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:536927). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263887	SCV002542571	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000645639	SCV003806927	uncertain significance	Familial cold autoinflammatory syndrome 2	2022-07-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4 supporting
CeGaT Center for Human Genetics Tuebingen	RCV003424224	SCV004142683	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing