rs104894714

Positions:

• chr19-40395495-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_181882.3(PRX):​c.2857C>T​(p.Arg953*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PRX NM_181882.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.653

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-40395495-G-A is Pathogenic according to our data. Variant chr19-40395495-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40395495-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.2857C>T	p.Arg953*	stop_gained	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.3142C>T	p.Arg1048*	stop_gained	7/7		NP_001398056.1
PRX	XM_017027047.2	c.2755C>T	p.Arg919*	stop_gained	4/4		XP_016882536.1
PRX	NM_020956.2	c.*3062C>T		3_prime_UTR_variant	6/6		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.2857C>T	p.Arg953*	stop_gained	7/7	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251340 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461894 Hom.: 0 Cov.: 99 AF XY: 0.0000110 AC XY: 8 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2024	Nonsense variant predicted to result in protein truncation, as the last 509 amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 22847150, 25326635, 24011642, 11133365, 31589614, 32376792, 36623372) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

PRX-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The PRX c.2857C>T variant is predicted to result in premature protein termination (p.Arg953*). This variant was reported in individuals with Charcot-Marie-Tooth Disease (homozygous, Castoro et al 2022. PubMed ID: 36623372; unspecified zygosity, Volodarsky et al. 2020. PubMed ID: 32376792) as well as in the compound heterozygous state in an individual with Dejerine-Sottas syndrome and in the heterozygous state in her unaffected son (Boerkoel et al. 2001. PubMed ID: 11133365). This variant is predicted to cause loss of normal protein function through the loss of the last 509 amino acids of the Periaxin protein, and other loss-of-function variants have been reported downstream of this variant (https://www.ncbi.nlm.nih.gov/clinvar; Human Gene Mutation Database (HGMD)). Nonsense variants in PRX are expected to be pathogenic. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Charcot-Marie-Tooth disease type 4F Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

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. -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRX protein in which other variant(s) (p.R1070*) have been determined to be pathogenic (PMID: 15197604, 16770524, 22847150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 4787). This premature translational stop signal has been observed in individuals with Dejerine-Sottas syndrome (PMID: 11133365). This variant is present in population databases (rs104894714, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg953*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 509 amino acid(s) of the PRX protein. -

Autosomal recessive Dejerine-Sottas syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.063	N
Vest4		0.70
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894714; hg19: chr19-40901402;