Submissions for variant NM_181882.3(PRX):c.2145T>A (p.Cys715Ter)

gnomAD frequency: 0.00006  dbSNP: rs104894707

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474032	SCV000551379	pathogenic	Charcot-Marie-Tooth disease type 4	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys715*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 747 amino acid(s) of the PRX protein. This variant is present in population databases (rs104894707, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 12112076). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4792). This variant disrupts a region of the PRX protein in which other variant(s) (p.Arg1070*) have been determined to be pathogenic (PMID: 15197604, 15469949, 16770524, 22847150, 26059842). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000760319	SCV000890175	likely pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 747 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12112076, 21840889, 20625412, 32085570)
CeGaT Center for Human Genetics Tuebingen	RCV000760319	SCV001247055	likely pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PRX: PVS1:Strong, PM2, PM3
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172756	SCV001335822	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000760319	SCV001880768	pathogenic	not provided	2020-11-12	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Revvity Omics, Revvity	RCV000760319	SCV002019536	pathogenic	not provided	2022-01-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000032004	SCV002581603	pathogenic	Charcot-Marie-Tooth disease type 4F	2022-07-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426489	SCV002727993	pathogenic	Inborn genetic diseases	2019-09-23	criteria provided, single submitter	clinical testing	The p.C715* variant (also known as c.2145T>A), located in coding exon 4 of the PRX gene, results from a T to A substitution at nucleotide position 2145. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration has been described homozygous in a brother and sister with Charcot-Marie-Tooth disease type 4F with disease onset prior to age 1 year and slow progression of disease. Additionally, unaffected siblings were either heterozygous or negative for the alteration (Takashima H et al. Ann. Neurol., 2002 Jun;51:709-15; Baets J et al. Brain, 2011 Sep;134:2664-76). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of PRX, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 747 amino acids of the protein, which accounts for over 50% of the protein. Additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. In addition, the truncated region is suggested to be responsible for targeting the protein for ubiquitin-mediated proteolysis (Takashima H et al. Ann. Neurol., 2002 Jun;51:709-15). Studies in mice have also shown protein disruption when this C-terminal region is deleted (Sherman DL et al. Wellcome Open Res, 2018 Mar;3:20). As such, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000032004	SCV000025235	pathogenic	Charcot-Marie-Tooth disease type 4F	2002-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000032004	SCV000054713	not provided	Charcot-Marie-Tooth disease type 4F		no assertion provided	literature only