19-40398770-G-T

Position:

• chr19-40398770-G-T

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.231C>A​(p.Tyr77Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRX NM_181882.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.301

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-40398770-G-T is Pathogenic according to our data. Variant chr19-40398770-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 958213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40398770-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRX	NM_181882.3	c.231C>A	p.Tyr77Ter	stop_gained	6/7	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.516C>A	p.Tyr172Ter	stop_gained	6/7		NP_001398056.1
PRX	NM_020956.2	c.231C>A	p.Tyr77Ter	stop_gained	6/6		NP_066007.1
PRX	XM_017027047.2	c.129C>A	p.Tyr43Ter	stop_gained	3/4		XP_016882536.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.231C>A	p.Tyr77Ter	stop_gained	6/7	1	NM_181882.3	ENSP00000326018	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PRX-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 21, 2024

Variant summary: PRX c.231C>A (p.Tyr77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 247616 control chromosomes. c.231C>A has been reported in the literature in multiple homozygous individuals affected with autosomal recessive CMT Type 4F, and segregates with disease within a large family (e.g. Zaman_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36833258). ClinVar contains an entry for this variant (Variation ID: 958213). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, no assertion criteria provided

research

Institute of Human Genetics, University of Ulm

Apr 12, 2022

- -

Gaucher disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 21, 2024

- -

Charcot-Marie-Tooth disease type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 28, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 958213). This premature translational stop signal has been observed in individual(s) with clinical indication for PRX genetic testing (PMID: 25614874). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr77*) in the PRX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRX are known to be pathogenic (PMID: 11133365). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.0021
FATHMM_MKL	Benign	0.46	N
MutationTaster	Benign	1.0	A;D
Vest4		0.76
GERP RS		-1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs752192677; hg19: chr19-40904677;