Submissions for variant NM_181882.3(PRX):c.2857C>T (p.Arg953Ter) (rs104894714)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000236836	SCV000255810	pathogenic	not provided	2019-03-11	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
GeneDx	RCV000236836	SCV000293535	pathogenic	not provided	2018-12-06	criteria provided, single submitter	clinical testing	The R953X variant in the PRX gene has been reported previously in the compound heterozygous state in an individual with Dejerine-Sottas Neuropathy (Boerkoel et al., 2001). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 509 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014). The R953X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R953X as a pathogenic variant.
Invitae	RCV000458979	SCV000551417	pathogenic	Charcot-Marie-Tooth disease type 4	2019-02-22	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the last exon of the PRX mRNA at codon 953 (p.Arg953*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 509 amino acids (~35%) of the PRX protein. This variant is present in population databases (rs104894714, ExAC 0.02%). This variant has been reported in a family affected with Dejerine-Sottas syndrome (PMID: 11133365). A different truncation downstream of this variant (p.R1070*) has been determined to be pathogenic (PMID: 15197604, 22847150, 16770524). This suggests that deletion of this region of the PRX protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000201141	SCV000807618	pathogenic	Charcot-Marie-Tooth disease, demyelinating, type 4F	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 14-year-old female with Charcot Marie Tooth disease. Heterozygotes are expected to be asymptomatic carriers.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000236836	SCV001247053	pathogenic	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001172752	SCV001335818	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
OMIM	RCV000005053	SCV000025229	pathogenic	Autosomal recessive Dejerine-Sottas syndrome	2001-02-01	no assertion criteria provided	literature only