ClinVar Genomic variation as it relates to human health
NM_000304.4(PMP22):c.353C>T (p.Thr118Met)
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.
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.
Likely pathogenic(1); Uncertain significance(12); Benign(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000304.4(PMP22):c.353C>T (p.Thr118Met)
Variation ID: 8431 Accession: VCV000008431.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p12 17: 15231047 (GRCh38) [ NCBI UCSC ] 17: 15134364 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 17, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000304.4:c.353C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000295.1:p.Thr118Met missense NM_001281455.2:c.353C>T NP_001268384.1:p.Thr118Met missense NM_001281456.2:c.353C>T NP_001268385.1:p.Thr118Met missense NM_153321.3:c.353C>T NP_696996.1:p.Thr118Met missense NM_153322.3:c.353C>T NP_696997.1:p.Thr118Met missense NR_104017.2:n.448C>T non-coding transcript variant NR_104018.2:n.348C>T non-coding transcript variant NC_000017.11:g.15231047G>A NC_000017.10:g.15134364G>A NG_007949.1:g.39281C>T LRG_263:g.39281C>T LRG_263t1:c.353C>T Q01453:p.Thr118Met - Protein change
- T118M
- Other names
- -
- Canonical SPDI
- NC_000017.11:15231046:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00284
The Genome Aggregation Database (gnomAD) 0.00378
The Genome Aggregation Database (gnomAD), exomes 0.00402
Exome Aggregation Consortium (ExAC) 0.00468
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 | ||
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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. |
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PMP22 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
403 | 521 |
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. |
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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Aug 22, 2023 | RCV000008946.27 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2009 | RCV000008945.11 | |
Uncertain significance (2) |
criteria provided, single submitter
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Oct 29, 2018 | RCV000032119.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 31, 2015 | RCV000194789.19 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 28, 2024 | RCV000197572.24 | |
Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV000224441.52 | |
Uncertain significance (2) |
criteria provided, single submitter
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- | RCV001027473.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 5, 2021 | RCV001507314.11 |
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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Uncertain significance
(Jul 31, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248536.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Neuropathy with Liability to Pressure Palsies
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000400718.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Likely benign
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth, Type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000400717.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Aug 24, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331367.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 10
Sex: mixed
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001337038.1
First in ClinVar: Jun 13, 2020 Last updated: Jun 13, 2020 |
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Uncertain significance
(Feb 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001712896.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Number of individuals with the variant: 16
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Uncertain significance
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003811204.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease, type I
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000254521.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 118 of the PMP22 protein (p.Thr118Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 118 of the PMP22 protein (p.Thr118Met). This variant is present in population databases (rs104894619, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in individuals and families with Charcot-Marie-Tooth disease type 1A (PMID: 16437560, 8988161, 8252046, 19691535, 21194947, 26392352). It has been reported as a dominantly inherited variant with reduced penetrance because both heterozygous affected (PMID: 21194947) and heterozygous unaffected individuals have been observed in several families (PMID: 8252046, 10586280). It has also been reported as a recessively inherited, partial loss of function allele based on observations of individuals with a more severe phenotype who presented as compound heterozygous for this allele along with a PMP22 deletion allele (PMID: 8252046, 26012543), and one individual with a more severe phenotype who was homozygous for this allele (PMID: 16437560). ClinVar contains an entry for this variant (Variation ID: 8431). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Functional studies show this variant is retained in the cytoplasm, albeit to a lesser extent compared to other PMP22 variants (PMID: 10078969). In addition, it leads to altered nuclei with an apoptotic-like phenotype when expressed in COS cells but not when co-expressed with wild type PMP22, which could be consistent with a recessive mode of inheritance in contrast to other PMP22 variants (PMID: 7649472). In summary, this variant has been reported to be dominantly inherited in individuals with CMT1A and it has also been reported to be recessively inherited in individuals with CMT1A who have presented with a more severe phenotype. This variant has also been shown to mildly disrupt protein function. However, the pathogenicity of this variant is much debated because it is present at a high frequency in the general population and it has been observed in unaffected and affected individuals within the same family. For these reasons, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493173.29
First in ClinVar: Jun 08, 2016 Last updated: Jun 17, 2024 |
Comment:
PMP22: BS2
Number of individuals with the variant: 17
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Uncertain Significance
(Jan 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280814.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Uncertain significance.
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Uncertain significance
(Jul 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary liability to pressure palsies
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000837683.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
This variant was also detected in the proband's father, who was found to have myopathic changes on EMG. This does not fully explain the proband's … (more)
This variant was also detected in the proband's father, who was found to have myopathic changes on EMG. This does not fully explain the proband's features but may be contributing to her phenotype. (less)
Number of individuals with the variant: 2
Clinical Features:
Waddling gait (present) , Temperature instability (present) , Small for gestational age (present) , Seizures (present) , Restrictive ventilatory defect (present) , Recurrent infections (present) … (more)
Waddling gait (present) , Temperature instability (present) , Small for gestational age (present) , Seizures (present) , Restrictive ventilatory defect (present) , Recurrent infections (present) , Ptosis (present) , Prolonged neonatal jaundice (present) , Progressive inability to walk (present) , Peripheral neuropathy (present) , Obstructive sleep apnea syndrome (present) , Nasal, dysarthic speech (present) , Myopathic facies (present) , Muscle weakness (present) , Motor delay (present) , Mitochondrial respiratory chain defects (present) , Migraine (present) , Intrauterine growth retardation (present) , Intermittent painful muscle spasms (present) , Impaired vibratory sensation (present) , Hyporeflexia (present) , Generalized hypotonia (present) , Gastrointestinal dysmotility (present) , Feeding difficulties (present) , Fatigue (present) , Dysautonomia (present) , Developmental stagnation (present) , Delayed speech and language development (present) , Decreased muscle mass (present) , Central sleep apnea syndrome (present) , Broad-based gait (present) , Bradycardia (present) , Birth length less than 3rd percentile (present) (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: White
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2018-07-02
Testing laboratory interpretation: Uncertain significance
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Uncertain significance
(Oct 29, 2018)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease, type IA
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429193.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary liability to pressure palsies
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001140306.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Uncertain significance
(Sep 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292667.15
First in ClinVar: Oct 05, 2015 Last updated: Nov 25, 2023 |
Comment:
Reported in an individual with CMT who had a pathogenic deletion of PMP22 on the opposite allele; the authors concluded p.(T118M) was likely an autosomal … (more)
Reported in an individual with CMT who had a pathogenic deletion of PMP22 on the opposite allele; the authors concluded p.(T118M) was likely an autosomal recessive allele because it was also identified in the individual's unaffected son (PMID: 8252046); It has been suggested that the p.(T118M) variant may modify disease severity in individuals with another PMP22 pathogenic variant (PMID: 26012543); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23891399, 11081809, 26392352, 31471994, 31127728, 31357912, 20301566, 32719652, 19067730, 21228398, 10078969, 7649472, 14502374, 28374912, 30675404, 30685714, 29655802, 27609586, 26102530, 31664448, 32513719, 32376792, 34426522, 26012543, 36539320, 36581210, 37703609, 19691535, 16437560, 10586280, 21194947, 8252046) (less)
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Uncertain significance
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000843297.6
First in ClinVar: Jun 08, 2016 Last updated: Jan 26, 2024 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants associated with autosomal dominant Charcot-Marie-Tooth disease (CMT) (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant does not segregate with disease in a manner consistent with dominant inheritance. Some literature suggests it may instead be a recessive and/or partial loss of function variant (PMID: 8252046, 16437560, 26012543, 30675404), thereby reducing severity of symptoms in patients with PMP22 duplications, while increasing severity in patients with PMP22 deletions. This variant has been reported to have a mild or lack of clinical effect in several heterozygous individuals (PMID: 8252046, 9452099, 10586280, 11081809), and also reported in one homozygous patient with a severe axonal neuropathy (PMID: 16437560). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicated this variant results in a reduction of protein transportation to the plasma membrane, with the majority sequestered in the endoplasmic reticulum. However, the effect seen in this assay was less severe than for known pathogenic variants (PMID: 10078969, 15537650, 26102530). (less)
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Uncertain significance
(Oct 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604882.5
First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024 |
Comment:
The PMP22 c.353C>T; p.Thr118Met variant (rs104894619) is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with liability to … (more)
The PMP22 c.353C>T; p.Thr118Met variant (rs104894619) is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with liability to pressure palsies (HNPP), although its clinical significance is controversial (Ho 2018, Keckarevic-Markovic 2009, Marques 2003, Nelis 1997, Roa 1993, Russo 2011, Seeman 1999, Shy 2006, Volodarsky 2021). Several reports of p.Thr118Met in affected families indicate possible recessive inheritance, as a more severe phenotype is observed in individuals carrying p.Thr118Met in trans to PMP22 deletions (Roa 1993), and at least one affected homozygote has been reported (Shy 2006). However, its inheritance pattern remains unclear, as both affected and unaffected heterozygous individuals have been also described (Ho 2018, Keckarevic-Markovic 2009, Nelis 1997, Roa 1993, Russo 2011). Further, in several families with both the p.Thr118Met variant and a pathogenic PMP22 duplication, the missense variant failed to segregate with disease (Marques 2003, Nelis 1997, Seeman 1999). The p.Thr118Met variant is found in the non-Finnish European population with an overall allele frequency of 0.66% (855/128884 alleles, including 3 homozygotes) in the Genome Aggregation Database (v2.1.1), which exceeds the estimated prevalence of CMT disease in the population (Theodom 2019). Computational analyses predict that this variant is deleterious (REVEL: 0.955). Consistent with predictions, functional studies indicate the variant protein fails to properly traffic to the plasma membrane (Schlebach 2015, Stefanski 2023). Due to conflicting information, and because a low penetrance effect cannot be ruled out, the clinical significance of the p.Thr118Met variant is uncertain at this time. References: Ho et al. T118M Variant of PMP22 Gene Presents with Painful Peripheral Neuropathy and Varying Charcot-Marie-Tooth Features: A Case Series and Review of the Literature. Case Rep Genet. 2018 Dec 25;2018:2618071. PMID: 30675404. Keckarevic-Markovic et al. Mutational analysis of GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in Serbian Charcot-Marie-Tooth patients. J Peripher Nerv Syst. 2009; 14(2): 125-136. PMID: 19691535. Marques et al. Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication. Braz J Med Biol Res. 2003; 36(10): 1403-1407. PMID: 14502374. Nelis et al. PMP22 Thr(118)Met: recessive CMT1 mutation or polymorphism? Nat Genet. 1997; 15(1): 13-14. PMID: 8988161. Roa et al. Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. Nat Genet. 1993; 5(2): 189-194. PMID: 8252046. Russo et al. Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul Disord. 2011; 21(2): 106-114. PMID: 21194947. Schlebach et al. Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22. J Am Chem Soc. 2015; 137(27): 8758-8768. PMID: 26102530. Seeman et al. Charcot-Marie-Tooth 1A: heterozygous T118M mutation over a CMT1A duplication has no influence on the phenotype. Ann N Y Acad Sci. 1999; 883: 485-489. PMID: 10586280. Shy et al. T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. Ann Neurol. 2006; 59(2): 358-364. PMID: 16437560. Stefanski KM et al. How T118M peripheral myelin protein 22 predisposes humans to Charcot-Marie-Tooth disease. J Biol Chem. 2023 Feb;299(2):102839. PMID: 36581210. Theadom et al. Prevalence of Charcot-Marie-Tooth disease across the lifespan: a population-based epidemiological study. BMJ Open. 2019 Jun 14;9(6):e029240. PMID: 31203252. Volodarsky et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. (less)
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Likely pathogenic
(Mar 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tip-toe gait
Affected status: yes
Allele origin:
unknown
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Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV001712107.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024 |
Comment:
The heterozygous variant c.353C> T p. (Thr118Met) was detected in the PMP22 gene [dbSNP rs104894619; frequency T = 0.468% (ExAC)]. In the literature [Shy (2006) … (more)
The heterozygous variant c.353C> T p. (Thr118Met) was detected in the PMP22 gene [dbSNP rs104894619; frequency T = 0.468% (ExAC)]. In the literature [Shy (2006) Ann Neurol 59: 358; Keckarevic-Markovic (2009) J Peripher Nerv Syst 14: 125; Russo (2011) Neuromuscul Disord 21: 106 and Ho (2018) Case Rep Genet 2018: 2618071] this variant is associated with hereditary neuropathies. However, the authors refer to numerous older studies in which it is controversially discussed and in some cases it is assigned an unclear clinical effect up to and including classification as a non-pathological polymorphism. These very inconsistent and controversial classifications are reflected in the databases ClinVar [4x pathogenic, 13x VUS, 3x likely / benign] and LOVD [7x pathogenic, 5x VUS, 2x likely benign]. A "reduced penetrance" [Russo (2011) Neuromuscul Disord 21: 106] of the proven variant is being discussed, since it was also demonstrated in control groups of the studies. In addition, a partial loss of function was observed for the protein affected by the variant depending on the genotype [Shy (2006) Ann Neurol 59: 358]. Modulating effects due to variants in other genes cannot be ruled out either. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. (less)
Observation 1:
Clinical Features:
Pes cavus (present) , limited range of motion of the upper ankle (present)
Age: 0-9 years
Sex: female
Method: Gene panel analysis
Observation 2:
Clinical Features:
Pes cavus (present) , limited range of motion of the upper ankle (present) , Exercise-induced leg cramps (present)
Age: 30-39 years
Sex: male
Method: Gene panel analysis
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Pathogenic
(Mar 01, 2009)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029155.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 24, 2015 |
Comment on evidence:
Roa et al. (1993) identified a patient with severe Charcot-Marie-Tooth disease type 1A (CMT1A; 118220) who was compound heterozygous for 2 mutations in the PMP22 … (more)
Roa et al. (1993) identified a patient with severe Charcot-Marie-Tooth disease type 1A (CMT1A; 118220) who was compound heterozygous for 2 mutations in the PMP22 gene: a 353C-T transition, resulting in a thr118-to-met (T118M) substitution, and a 1.5-Mb deletion (601097.0004). The findings were consistent with autosomal recessive inheritance. A son heterozygous for the T118M mutation had no signs of neuropathy, while 2 other sons heterozygous for the 1.5-Mb deletion had hereditary neuropathy with liability to pressure palsies (HNPP; 162500). The deletion was demonstrated by FISH in the severely affected patient and in her affected sons. Bathke et al. (1996) reported a man with CMT1A who was compound heterozygous for T118M and a 1.5-Mb deletion in the PMP22 gene. His unaffected mother was heterozygous for the T118M substitution. The T118M substitution was not identified in 104 healthy control individuals. Nelis et al. (1997) presented evidence suggesting that the T118M substitution is not pathogenic. Although they identified heterozygosity for T118M in a single patient with CMT1, the patient's unaffected father also carried the substitution. The T118M substitution was also identified in the unaffected father of another family with CMT1, whereas the affected patient in that family did not have the substitution. The T118M substitution was also identified in the heterozygous state in 10 of 262 controls from northern Sweden, yielding an allele frequency of 1.9%. Niedrist et al. (2009) identified a T118M substitution in cis with a truncating PMP22 mutation (601097.0021) in a 20-year-old man with severe CMT1A. The phenotype was attributed to the truncating mutation because the truncated protein would not contain the downstream T118M substitution. Analysis of the parents showed that the clinically unaffected father was heterozygous for the T118M substitution, which suggested that the T118M substitution may not be pathogenic, although electrophysiologic studies were not performed on the father. Shy et al. (2006) reported 3 unrelated individuals with a mild demyelinating neuropathy similar to HNPP who were heterozygous for the T118M substitution. Two members of a fourth kindred with mild CMT1A and electrophysiologic features of HNPP had the T118M substitution and a duplication of the PMP22 gene (601097.0001). In a fifth family, a child with early-onset severe axonal neuropathy was found to be homozygous for the T118M mutation. Although she had severe denervation, she did not have overt demyelination. Her unaffected parents, who had electrophysiologic features consistent with HNPP, were both heterozygous for T118M. Shy et al. (2006) concluded that the T118M substitution is a pathogenic mutation resulting in a partial loss of protein function. The authors suggested that the corresponding phenotypes are due to a PMP22 dosage effect; T118M may thus act as a dominant allele with reduced penetrance. (less)
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Pathogenic
(Mar 01, 2009)
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no assertion criteria provided
Method: literature only
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NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053463.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 24, 2015 |
Comment on evidence:
Roa et al. (1993) identified a patient with severe Charcot-Marie-Tooth disease type 1A (CMT1A; 118220) who was compound heterozygous for 2 mutations in the PMP22 … (more)
Roa et al. (1993) identified a patient with severe Charcot-Marie-Tooth disease type 1A (CMT1A; 118220) who was compound heterozygous for 2 mutations in the PMP22 gene: a 353C-T transition, resulting in a thr118-to-met (T118M) substitution, and a 1.5-Mb deletion (601097.0004). The findings were consistent with autosomal recessive inheritance. A son heterozygous for the T118M mutation had no signs of neuropathy, while 2 other sons heterozygous for the 1.5-Mb deletion had hereditary neuropathy with liability to pressure palsies (HNPP; 162500). The deletion was demonstrated by FISH in the severely affected patient and in her affected sons. Bathke et al. (1996) reported a man with CMT1A who was compound heterozygous for T118M and a 1.5-Mb deletion in the PMP22 gene. His unaffected mother was heterozygous for the T118M substitution. The T118M substitution was not identified in 104 healthy control individuals. Nelis et al. (1997) presented evidence suggesting that the T118M substitution is not pathogenic. Although they identified heterozygosity for T118M in a single patient with CMT1, the patient's unaffected father also carried the substitution. The T118M substitution was also identified in the unaffected father of another family with CMT1, whereas the affected patient in that family did not have the substitution. The T118M substitution was also identified in the heterozygous state in 10 of 262 controls from northern Sweden, yielding an allele frequency of 1.9%. Niedrist et al. (2009) identified a T118M substitution in cis with a truncating PMP22 mutation (601097.0021) in a 20-year-old man with severe CMT1A. The phenotype was attributed to the truncating mutation because the truncated protein would not contain the downstream T118M substitution. Analysis of the parents showed that the clinically unaffected father was heterozygous for the T118M substitution, which suggested that the T118M substitution may not be pathogenic, although electrophysiologic studies were not performed on the father. Shy et al. (2006) reported 3 unrelated individuals with a mild demyelinating neuropathy similar to HNPP who were heterozygous for the T118M substitution. Two members of a fourth kindred with mild CMT1A and electrophysiologic features of HNPP had the T118M substitution and a duplication of the PMP22 gene (601097.0001). In a fifth family, a child with early-onset severe axonal neuropathy was found to be homozygous for the T118M mutation. Although she had severe denervation, she did not have overt demyelination. Her unaffected parents, who had electrophysiologic features consistent with HNPP, were both heterozygous for T118M. Shy et al. (2006) concluded that the T118M substitution is a pathogenic mutation resulting in a partial loss of protein function. The authors suggested that the corresponding phenotypes are due to a PMP22 dosage effect; T118M may thus act as a dominant allele with reduced penetrance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Hereditary liability to pressure palsies
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000929043.1
First in ClinVar: Jul 29, 2019 Last updated: Jul 29, 2019 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: provider interpretation
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
inherited
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Inherited Neuropathy Consortium
Accession: SCV001190043.1
First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020 |
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary liability to pressure palsies
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000086759.3
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease, type IA
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000055665.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly. | Pomarino D | Global medical genetics | 2023 | PMID: 37091313 |
How T118M peripheral myelin protein 22 predisposes humans to Charcot-Marie-Tooth disease. | Stefanski KM | The Journal of biological chemistry | 2023 | PMID: 36581210 |
The genetic structure of the Turkish population reveals high levels of variation and admixture. | Kars ME | Proceedings of the National Academy of Sciences of the United States of America | 2021 | PMID: 34426522 |
Peripheral myelin protein 22 preferentially partitions into ordered phase membrane domains. | Marinko JT | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 32513719 |
Hereditary Neuropathy with Liability to Pressure Palsies. | Adam MP | - | 2020 | PMID: 20301566 |
Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation. | McCreary D | JAMA network open | 2019 | PMID: 31664448 |
T118M Variant of PMP22 Gene Presents with Painful Peripheral Neuropathy and Varying Charcot-Marie-Tooth Features: A Case Series and Review of the Literature. | Ho KWD | Case reports in genetics | 2018 | PMID: 30675404 |
Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. | Antoniadi T | BMC medical genetics | 2015 | PMID: 26392352 |
Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22. | Schlebach JP | Journal of the American Chemical Society | 2015 | PMID: 26102530 |
Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion. | Jerath NU | Muscle & nerve | 2015 | PMID: 26012543 |
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2015 | PMID: 20301384 |
PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. | van Paassen BW | Orphanet journal of rare diseases | 2014 | PMID: 24646194 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Variable phenotypes are associated with PMP22 missense mutations. | Russo M | Neuromuscular disorders : NMD | 2011 | PMID: 21194947 |
The 5' regulatory sequence of the PMP22 in the patients with Charcot-Marie-Tooth disease. | Sinkiewicz-Darol E | Acta biochimica Polonica | 2010 | PMID: 20842290 |
Mutational analysis of GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in Serbian Charcot-Marie-Tooth patients. | Keckarevic-Markovic M | Journal of the peripheral nervous system : JPNS | 2009 | PMID: 19691535 |
Severe phenotype with cis-acting heterozygous PMP22 mutations. | Niedrist D | Clinical genetics | 2009 | PMID: 19067730 |
T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. | Shy ME | Annals of neurology | 2006 | PMID: 16437560 |
Glycan-independent role of calnexin in the intracellular retention of Charcot-Marie-tooth 1A Gas3/PMP22 mutants. | Fontanini A | The Journal of biological chemistry | 2005 | PMID: 15537650 |
Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication. | Marques W Jr | Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas | 2003 | PMID: 14502374 |
PMP22 Thr118Met is not a clinically relevant CMT1 marker. | Young P | Journal of neurology | 2000 | PMID: 11081809 |
Charcot-Marie-Tooth 1A: heterozygous T118M mutation over a CMT1A duplication has no influence on the phenotype. | Seeman P | Annals of the New York Academy of Sciences | 1999 | PMID: 10586280 |
Impaired intracellular trafficking is a common disease mechanism of PMP22 point mutations in peripheral neuropathies. | Naef R | Neurobiology of disease | 1999 | PMID: 10078969 |
Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1). | Sorour E | Human mutation | 1998 | PMID: 9452099 |
PMP22 Thr(118)Met: recessive CMT1 mutation or polymorphism? | Nelis E | Nature genetics | 1997 | PMID: 8988161 |
Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A. | Fabbretti E | Genes & development | 1995 | PMID: 7649472 |
Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A. | Roa BB | Nature genetics | 1993 | PMID: 8252046 |
Bathke, K. D., Ekici, A., Liehr, T., Grehl, H., Lupski, J. R., Neundorfer, B., Rautenstrauss, B. The hemizygous thr118met amino acid exchange in peripheral myelin protein 22: recessive Charcot-Marie-Tooth (CMT) disease type 1 mutation or polymorphism? (Abstract) Am. J. Hum. Genet. 59 (suppl.): A248-only, 1996. | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMP22 | - | - | - | - |
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Text-mined citations for rs104894619 ...
HelpRecord last updated Jun 23, 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.