Submissions for variant NM_181882.3(PRX):c.823C>A (p.Leu275Ile)

gnomAD frequency: 0.00108  dbSNP: rs200033507

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195707	SCV000255227	likely benign	Charcot-Marie-Tooth disease type 4	2025-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094576	SCV000413245	uncertain significance	Charcot-Marie-Tooth disease 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 Center for Human Genetics Tuebingen	RCV000415792	SCV000493487	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PRX: BP1
GeneDx	RCV000415792	SCV000583132	likely benign	not provided	2020-09-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25025039, 26257172, 26392352, 32376792)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000415792	SCV000604941	uncertain significance	not provided	2019-09-13	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	RCV000493878	SCV000614816	benign	not specified	2023-12-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001449601	SCV001652703	uncertain significance	Tip-toe gait	2021-04-27	criteria provided, single submitter	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Mayo Clinic Laboratories, Mayo Clinic	RCV000415792	SCV001713815	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426952	SCV002681847	uncertain significance	Inborn genetic diseases	2023-10-24	criteria provided, single submitter	clinical testing	The c.823C>A (p.L275I) alteration is located in exon 7 (coding exon 4) of the PRX gene. This alteration results from a C to A substitution at nucleotide position 823, causing the leucine (L) at amino acid position 275 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000415792	SCV001809704	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000415792	SCV001924551	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001094576	SCV004228971	not provided	Charcot-Marie-Tooth disease type 4F		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 07-24-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV003917822	SCV004733497	likely benign	PRX-related disorder	2020-08-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).