ClinVar Miner

Submissions for variant NM_144687.4(NLRP12):c.653C>T (p.Ala218Val)

gnomAD frequency: 0.00001  dbSNP: rs749659859
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000809496 SCV000949648 uncertain significance Familial cold autoinflammatory syndrome 2 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 218 of the NLRP12 protein (p.Ala218Val). This variant is present in population databases (rs749659859, gnomAD 0.006%). 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: 653688). 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 not expected to disrupt NLRP12 protein function with a negative 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000809496 SCV001472611 uncertain significance Familial cold autoinflammatory syndrome 2 2020-01-20 criteria provided, single submitter clinical testing The NLRP12 c.653C>T; p.Ala218Val variant (rs749659859), to our knowledge, is not reported in the medical literature. The variant is listed in the ClinVar database (Variation ID: 653688) and is reported in the general population with an overall allele frequency of 0.0008% (2/251,148 alleles) in the Genome Aggregation Database. The alanine at codon 218 is highly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ala218Val variant is uncertain at this time.

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