19-40396062-GA-G

Position:

• chr19-40396062-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000324001.8(PRX):​c.2289del​(p.Asp765ThrfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRX ENST00000324001.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.14

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 18 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 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-40396062-GA-G is Pathogenic according to our data. Variant chr19-40396062-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40396062-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.2289del	p.Asp765ThrfsTer10	frameshift_variant	7/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.2574del	p.Asp860ThrfsTer10	frameshift_variant	7/7		NP_001398056.1
PRX	XM_017027047.2	c.2187del	p.Asp731ThrfsTer10	frameshift_variant	4/4		XP_016882536.1
PRX	NM_020956.2	c.*2494del		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.2289del	p.Asp765ThrfsTer10	frameshift_variant	7/7	1	NM_181882.3	ENSP00000326018	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461820 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 06, 2014

The Asp765ThrfsX10 variant in PRX has been reported in one compound heterozygous individual with peripheral neuropathy (Boerkoel 2011). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 765 and leads to a premature termination codon 10 amino acids downstream. This premature termination codon occurs in the last exon and therefore may escape nonsense mediated decay (NMD), resulting in a truncated protein. Importantly, several other truncating variants have been identified downstream of this position in several individuals with Charcot-Marie-Tooth disease type 4F (Boerkoel 2011, Kijima 2004, Marchesi 2010, Sivera 2013) indicating truncating variants in the last exon of PRX are not tolerated. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance (http://pcpgm.partners.org/LMM). -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2022

This premature translational stop signal has been observed in individual(s) with PRX-related conditions (PMID: 11133365). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp765Thrfs*10) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 697 amino acid(s) of the PRX protein. 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.Gln1169*) have been determined to be pathogenic (Invitae). 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: 208606). This variant is also known as V763fsX774. -

Autosomal recessive Dejerine-Sottas syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

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: rs797045102; hg19: chr19-40901969;