ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.3043A>G (p.Lys1015Glu) (rs771315000)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222974 SCV000278966 uncertain significance not provided 2014-02-02 criteria provided, single submitter clinical testing To our knowledge, the K1015E missense substitution has neither been published as a mutation, nor reported as a benign polymorphism. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K1015E represents a non-conservative amino acid substitution as a positively-charged Lysine residue is replaced with a negatively-charged Glutamic Acid residue. However, this substitution occurs at a position in the NLRP3 protein that is only moderately conserved among species and is not located in the NACHT/NBD domain, which is the domain where the vast majority of NLRP3 disease-associated mutations have been identified. Therefore, based on the currently available information, it is unclear whether K1015E is a disease-causing mutation or a rare benign variant.
Invitae RCV000690719 SCV000818419 uncertain significance Cryopyrin associated periodic syndrome 2019-06-10 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1015 of the NLRP3 protein (p.Lys1015Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs771315000, ExAC 0.001%). This variant has not been reported in the literature in individuals with NLRP3-related disease. ClinVar contains an entry for this variant (Variation ID: 234308). 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.
Illumina Clinical Services Laboratory,Illumina RCV001102298 SCV001258965 uncertain significance Chronic infantile neurological, cutaneous and articular syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001102299 SCV001258966 uncertain significance Familial amyloid nephropathy with urticaria AND deafness 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001102300 SCV001258967 uncertain significance Familial cold urticaria 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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