ClinVar Miner

Submissions for variant NM_014646.2(LPIN2):c.1796C>T (p.Pro599Leu) (rs372850864)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000325500 SCV000408474 uncertain significance Majeed 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.
GeneDx RCV000755297 SCV000573287 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing The P599L variant has been observed in a patient with an auto-inflammatory disorder; however that patient had another previously-observed variant which was unspecified (Rusmini et al., 2015). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). P599L 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 that is not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755297 SCV000604122 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing The LPIN2 c.1796C>T;p.Pro599Leu variant (rs372850864) has been described in the medical literature in at least one individual with a clinical diagnosis of systemic auto-inflammatory disease (Rusmini 2016). The variant is listed in the ClinVar database (Variation ID: 326636) and in the Genome Aggregation Database in 14 out of 277170 alleles, indicating it is not a common polymorphism. The proline at this position is moderately conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. If this variant is later determined to be pathogenic, this variant individual may be a carrier of Majeed syndrome (OMIM#605519). References: Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7.
Invitae RCV000325500 SCV000766479 uncertain significance Majeed syndrome 2019-06-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 599 of the LPIN2 protein (p.Pro599Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs372850864, ExAC 0.004%). This variant has been reported in a study of individuals affected with systemic auto-inflammatory diseases; however, the phenotype of the individual who harbors this variant is unknown (PMID: 26386126). ClinVar contains an entry for this variant (Variation ID: 326636). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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.