Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004794, PMID:15197604). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_181882.3(PRX):c.3208C>T (p.Arg1070Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_181882.3(PRX):c.3208C>T (p.Arg1070Ter)
Variation ID: 4794 Accession: VCV000004794.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 40395144 (GRCh38) [ NCBI UCSC ] 19: 40901051 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Sep 16, 2024 May 25, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_181882.3:c.3208C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_870998.2:p.Arg1070Ter nonsense NM_020956.2:c.*3413C>T 3 prime UTR NC_000019.10:g.40395144G>A NC_000019.9:g.40901051G>A NG_007979.1:g.23221C>T NG_051224.1:g.78C>T LRG_265:g.23221C>T LRG_265t1:c.*3413C>T LRG_265t2:c.3208C>T LRG_265p2:p.Arg1070Ter - Protein change
- R1070*
- Other names
- -
- Canonical SPDI
- NC_000019.10:40395143:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PRX | - | - |
GRCh38 GRCh37 |
1258 | 1341 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2022 | RCV000005061.9 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Dec 1, 2020 | RCV000032006.6 | |
| Pathogenic (2) |
criteria provided, single submitter
|
May 25, 2023 | RCV000701391.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
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Pathogenic
(Oct 22, 2012)
|
criteria provided, single submitter
Method: research
|
Dejerine-Sottas disease
Affected status: yes
Allele origin:
inherited
|
Centre for Translational Omics - GOSgene, University College London
Accession: SCV000212112.2
First in ClinVar: May 01, 2015 Last updated: Jul 31, 2015 |
Clinical Features:
demyelinating neuropathy (present)
Sex: male
Geographic origin: Bangladeshi
|
|
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Pathogenic
(Dec 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4F
Affected status: yes
Allele origin:
germline
|
CMT Laboratory, Bogazici University
Accession: SCV001548314.1
First in ClinVar: Apr 03, 2021 Last updated: Apr 03, 2021 |
Number of individuals with the variant: 1
Family history: yes
Secondary finding: no
|
|
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Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dejerine-Sottas disease
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058313.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004794, PMID:15197604). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Central hypotonia (present) , Global developmental delay (present)
|
|
|
Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000830191.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4794). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4794). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 15197604, 15469949, 16770524, 22847150, 26059842). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894708, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg1070*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 392 amino acid(s) of the PRX protein. (less)
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Pathogenic
(Nov 01, 2012)
|
no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4F
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025237.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2024 |
Comment on evidence:
In 3 unrelated Japanese patients with Charcot-Marie-Tooth disease type 4F (CMT4F; 614895), Kijima et al. (2004) identified a homozygous 3208C-T transition in the PRX gene, … (more)
In 3 unrelated Japanese patients with Charcot-Marie-Tooth disease type 4F (CMT4F; 614895), Kijima et al. (2004) identified a homozygous 3208C-T transition in the PRX gene, resulting in an arg1070-to-ter (R1070X) mutation. The patients presented with early onset and slowly progressive distal motor and sensory neuropathy. All 3 patients were born of healthy, consanguineous parents. Two of the patients also had an affected sib. On sural nerve biopsy, 1 patient had atypical onion bulb formation, the second had more typical onion bulb formation, and the third had onion bulb and tomacula formation. Otagiri et al. (2006) reported a Japanese girl with CMT4F who was compound heterozygous for the R1070X mutation and a 10-bp insertion (394_395insATCCAGAGTC, Leu132fsTer153; 605725.0009) in the PRX gene. Each of her unaffected parents was heterozygous for 1 of the mutations. Haplotype analysis of this family and the 3 Japanese families reported by Kijima et al. (2004) suggested that the common R1070X mutation was a result of a mutation hotspot, not a founder effect. Tokunaga et al. (2012) reported 2 unrelated Japanese patients with adult-onset CMT4F due to a homozygous R1070X mutation. One patient developed mild distal muscle wasting and sensory disturbance in all limbs at age 50 years. The disorder was slowly progressive, and she could still walk independently at age 63 despite having pes cavus. Sural nerve biopsy showed moderate demyelination and complex onion bulb formation. The other patient developed lower limb weakness at age 37 years. At age 47, he could walk with a walking vehicle. Other features included scoliosis and areflexia. Sural nerve biopsy showed myelin thinning and onion bulbs. Motor nerve conduction velocities in the median nerve were 20 m/s in both patients. Tokunaga et al. (2012) emphasized the late onset and relatively mild phenotype in these patients. (less)
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease type 4
Affected status: yes
Allele origin:
germline
|
Genesis Genome Database
Accession: SCV000999622.1
First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019 |
|
|
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not provided
(-)
|
no classification provided
Method: literature only
|
Charcot-Marie-Tooth disease type 4F
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000054715.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4794). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 15197604, 15469949, 16770524, 22847150, 26059842). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894708, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg1070*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 392 amino acid(s) of the PRX protein.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004794, PMID:15197604). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4794). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 15197604, 15469949, 16770524, 22847150, 26059842). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894708, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg1070*) in the PRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 392 amino acid(s) of the PRX protein.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The use of whole-exome sequencing to disentangle complex phenotypes. | Williams HJ | European journal of human genetics : EJHG | 2016 | PMID: 26059842 |
| Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2016 | PMID: 20301641 |
| Late-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation. | Tokunaga S | Neurogenetics | 2012 | PMID: 22847150 |
| Four novel cases of periaxin-related neuropathy and review of the literature. | Marchesi C | Neurology | 2010 | PMID: 21079185 |
| Periaxin mutation in Japanese patients with Charcot-Marie-Tooth disease. | Otagiri T | Journal of human genetics | 2006 | PMID: 16770524 |
| Clinicopathological and genetic study of early-onset demyelinating neuropathy. | Parman Y | Brain : a journal of neurology | 2004 | PMID: 15469949 |
| Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease. | Kijima K | Journal of human genetics | 2004 | PMID: 15197604 |
| A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. | Guilbot A | Human molecular genetics | 2001 | PMID: 11157804 |
Text-mined citations for rs104894708 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.