ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.950C>T (p.Pro317Leu) (rs180177462)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213159 SCV000279569 uncertain significance not provided 2016-02-10 criteria provided, single submitter clinical testing The P317L variant has been previously published as a pathogenic variant associated with Crypryrin-associated periodic syndrome (CAPS) and Muckle Wells syndrome (Wakhlu et al., 2015) with limited data to fully support pathogenicity. The NHLBI Exome Sequencing Project reports P317L was observed in 1 of 4406 alleles (0.02%) from individuals of African American background, and the 1000 Genomes Project Consortium reports it was observed in 1 of 198 alleles (0.51%) from individuals of Kinh background in Ho Chi Minh City, Vietnam. Thus, P317L may be a rare variant in these populations. The P317L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position in the NACHT domain that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. However, missense variants in nearby residues (E313K, H314P, I315V) have been reported in the Human Gene Mutation Database in association with Muckle Wells syndrome and CAPS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000378566 SCV000356933 likely benign Chronic infantile neurological, cutaneous and articular syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000084253 SCV000356934 likely benign Familial cold urticaria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000344447 SCV000356935 likely benign Familial amyloid nephropathy with urticaria AND deafness 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001195579 SCV001365974 likely benign not specified 2019-05-24 criteria provided, single submitter clinical testing The p.Pro317Leu variant in NLRP3 is classified as likely benign because it has been identified in 0.059% (18/31012) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Pro317Leu variant may not impact the protein. ACMG/AMP Criteria applied: BS1, BP4.
Invitae RCV001226114 SCV001398414 uncertain significance Cryopyrin associated periodic syndrome 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 317 of the NLRP3 protein (p.Pro317Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs180177462, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with cryopyrin-associated periodic syndrome (PMID: 25979514). This variant is also known as p.Pro315Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 97990). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084253 SCV000116389 not provided Familial cold urticaria no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.