ClinVar Miner

Submissions for variant NM_020956.2(PRX):c.*1028C>A (rs200033507)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195707 SCV000255227 likely benign Charcot-Marie-Tooth disease type 4 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094576 SCV000413245 uncertain significance Charcot-Marie-Tooth disease, demyelinating, type 4F 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415792 SCV000493487 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000493878 SCV000583132 uncertain significance not specified 2017-05-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PRX gene. The L275I variant has been previously reported in two families with CMT who also had another variant on the opposite allele; however, the L275I variant did not segregate with disease in either family, leading the authors to conclude that it is not pathogenic (Hoyer et al., 2014). The L275I variant is observed in 7/4404 (0.2%) alleles from individuals of non-Finnish European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L275I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, 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 RCV000493878 SCV000604941 uncertain significance not specified 2018-12-26 criteria provided, single submitter clinical testing The PRX c.823C>A; p.Leu275Ile variant (rs200033507), is reported in the literature in individuals affected with Charcot-Marie-Tooth (CMT) disease or hereditary motor neuropathy, but did not segregate with disease in at least two families, suggesting the variant is not causative for disease (Antoniadi 2015, Hoyer 2014). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 216836), and is found in the non-Finnish European population with an allele frequency of 0.22% (153/69,546 alleles) in the Genome Aggregation Database. The leucine at codon 275 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. Thus, based on available information, the clinical significance of the p.Leu275Ile variant cannot be determined with certainty. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84. Hoyer et al. Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. Biomed Res Int. 2014 2014: 210401.
Athena Diagnostics Inc RCV000493878 SCV000614816 likely benign not specified 2016-09-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000415792 SCV000856117 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173081 SCV001336157 likely benign Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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