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

Total submissions: 7

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