ClinVar Genomic variation as it relates to human health
NC_000017.11:g.(?_14440201)_(15475424_?)dup
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NC_000017.11:g.(?_14440201)_(15475424_?)dup
Variation ID: 8427 Accession: VCV000008427.2
- Type and length
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Duplication, -
- Location
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Cytogenetic: 17p11.2 -
- 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 May 1, 2015 Oct 18, 2012 - HGVS
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Nucleotide Protein Molecular
consequenceNC_000017.11:g.(?_14440201)_(15475424_?)dup - Protein change
- Other names
- 1.4-MB DUP
- 1.5-Mb duplication at 17p11.2
- Canonical SPDI
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
- Comment on variant
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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Pathogenic (2) |
no assertion criteria provided
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Oct 18, 2012 | RCV000008938.5 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2009 | RCV000008939.4 |
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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pathologic
(Oct 18, 2012)
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no assertion criteria provided
Method: curation
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Charcot-Marie-Tooth Neuropathy Type 1
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000055639.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Sep 01, 2009)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029148.3
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015 |
Comment on evidence:
Lupski et al. (1991) found a DNA duplication on chromosome 17p as the apparent basis of Charcot-Marie-Tooth disease type 1A (CMT1A; 118220). They showed complete … (more)
Lupski et al. (1991) found a DNA duplication on chromosome 17p as the apparent basis of Charcot-Marie-Tooth disease type 1A (CMT1A; 118220). They showed complete linkage and association of this duplication in 7 multigenerational CMT1A pedigrees and in several isolated, unrelated patients. Pulsed field gel electrophoresis of genomic DNA from CMT1 patients of different ethnic origins showed a novel SacII fragment of 500 kb, and this fragment showed mendelian inheritance. The duplication was also directly visualized by 2-color FISH in interphase nuclei. Lupski et al. (1991) found that a severely affected person, the product of a first-cousin marriage (Killian and Kloepfer, 1979), was homozygous for the duplication. Onset was before age 1 year and reduction in motor nerve conduction velocity was severe. A less severely affected sister was heterozygous for the duplication. The finding implicated a local DNA duplication, a segmental trisomy, as a novel mechanism for an autosomal dominant human disease. The classic example of a DNA duplication is the Bar locus in Drosophila melanogaster as described by Bridges (1936). Lupski et al. (1991) noted that failure to recognize the molecular duplication could lead to misinterpretation of marker genotypes for affected persons with identification of false recombinance and incorrect localization of the disease locus. The duplication was likewise demonstrated by Raeymaekers et al. (1991) who, like Lupski et al. (1991), concluded that the duplication is probably the mutation responsible for the disease. The duplication was demonstrated in locus D17S122 (probe VAW409R3). Using pulsed field gel electrophoresis analysis, Hoogendijk et al. (1991) estimated the minimal size of the duplicated region in CMT1A patients to be 1,100 kb. While trying to determine the size of the chromosome 17 duplication, Raeymaekers et al. (1992) showed that on the genetic map the duplicated markers span a minimal distance of 10 cM, while on the physical map they are present in the same NotI restriction fragment of 1,150 kb. The discrepancy between the genetic and physical map distances suggests that the 17p11.2 region is highly prone to recombination. The authors suggested that the high recombination rate may be a contributing factor to the genetic instability of the region. Valentijn et al. (1992) used 2-color fluorescence in situ hybridization (FISH) on interphase nuclei of fibroblasts to demonstrate that the duplication is a direct tandem repeat: they observed red-green for the normal chromosome and red-green-red-green for the chromosome with the duplication; in none of the nuclei analyzed was the order red-green-green-red or green-red-red-green, compatible with an inverted repeat. The authors suggested that those affected families in which there is no duplication of the PMP22 gene likely represent intragenic mutations comparable to those in the Trembler mouse. Hoogendijk et al. (1992) found the chromosome 17 duplication as a de novo mutation in 9 of 10 sporadic patients with HMSN I. During a population survey of CMT1 in south Wales, MacMillan et al. (1992) found duplication of locus D17S122, recognized by a DNA probe that detects an MspI polymorphism, in 10 of 11 families selected only by clinical criteria. Trisomy for this chromosome region is demonstrated either by the presence of 3 alleles or a dosage effect when only 2 of the alleles are present. The 1 family without trisomy did not differ in type or severity of disease from the other families. Lupski et al. (1992) described a patient with a cytogenetically visible duplication, dup(17)(p11.2p12). Molecular analysis demonstrated that this patient had duplications of all the DNA markers duplicated in other cases of CMT1A as well as of markers both proximal and distal to the CMT1A duplication. Upadhyaya et al. (1993) reported another instance of a microscopically visible duplication of 17p12-p11.2 in association with CMT1A. Wise et al. (1993) used 3 molecular methods to search for the CMT1A DNA duplication in 75 unrelated patients diagnosed clinically with CMT and evaluated by electrophysiologic methods. The CMT1A duplication was found in 68% of the 63 unrelated CMT patients with electrophysiologic studies consistent with CMT type 1. The CMT1A duplication was detected as a de novo event in 2 CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 were found not to have the CMT1A duplication. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment by pulsed field gel electrophoresis. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of new mutations, Wise et al. (1993) concluded that a molecular test for the CMT1A DNA duplication is useful in the differential diagnosis of patients with peripheral neuropathies. In a 2-year-old boy with severe demyelinating CMT, Meggouh et al. (2005) identified compound heterozygosity for 2 mutations: the PMP22 duplication and a mutation in the LITAF gene (G112S; 603795.0001), which causes CMT1C (601098). Each parent was heterozygous for 1 of the mutations, and each had pes cavus and reduced nerve conduction velocities consistent with mild CMT. Meggouh et al. (2005) concluded that the cooccurrence of both mutations resulted in the more severe phenotype in the proband. In 3 members of a 4-generation family with Roussy-Levy syndrome (180800), Auer-Grumbach et al. (1998) identified the CMT1A PMP22 duplication. Miltenberger-Miltenyi et al. (2009) identified the CMT1A PMP22 1.4-Mb duplication in 79 (31.6%) of 250 unrelated Austrian patients with CMT. (less)
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Pathogenic
(Sep 01, 2009)
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no assertion criteria provided
Method: literature only
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ROUSSY-LEVY SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053460.3
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015 |
Comment on evidence:
Lupski et al. (1991) found a DNA duplication on chromosome 17p as the apparent basis of Charcot-Marie-Tooth disease type 1A (CMT1A; 118220). They showed complete … (more)
Lupski et al. (1991) found a DNA duplication on chromosome 17p as the apparent basis of Charcot-Marie-Tooth disease type 1A (CMT1A; 118220). They showed complete linkage and association of this duplication in 7 multigenerational CMT1A pedigrees and in several isolated, unrelated patients. Pulsed field gel electrophoresis of genomic DNA from CMT1 patients of different ethnic origins showed a novel SacII fragment of 500 kb, and this fragment showed mendelian inheritance. The duplication was also directly visualized by 2-color FISH in interphase nuclei. Lupski et al. (1991) found that a severely affected person, the product of a first-cousin marriage (Killian and Kloepfer, 1979), was homozygous for the duplication. Onset was before age 1 year and reduction in motor nerve conduction velocity was severe. A less severely affected sister was heterozygous for the duplication. The finding implicated a local DNA duplication, a segmental trisomy, as a novel mechanism for an autosomal dominant human disease. The classic example of a DNA duplication is the Bar locus in Drosophila melanogaster as described by Bridges (1936). Lupski et al. (1991) noted that failure to recognize the molecular duplication could lead to misinterpretation of marker genotypes for affected persons with identification of false recombinance and incorrect localization of the disease locus. The duplication was likewise demonstrated by Raeymaekers et al. (1991) who, like Lupski et al. (1991), concluded that the duplication is probably the mutation responsible for the disease. The duplication was demonstrated in locus D17S122 (probe VAW409R3). Using pulsed field gel electrophoresis analysis, Hoogendijk et al. (1991) estimated the minimal size of the duplicated region in CMT1A patients to be 1,100 kb. While trying to determine the size of the chromosome 17 duplication, Raeymaekers et al. (1992) showed that on the genetic map the duplicated markers span a minimal distance of 10 cM, while on the physical map they are present in the same NotI restriction fragment of 1,150 kb. The discrepancy between the genetic and physical map distances suggests that the 17p11.2 region is highly prone to recombination. The authors suggested that the high recombination rate may be a contributing factor to the genetic instability of the region. Valentijn et al. (1992) used 2-color fluorescence in situ hybridization (FISH) on interphase nuclei of fibroblasts to demonstrate that the duplication is a direct tandem repeat: they observed red-green for the normal chromosome and red-green-red-green for the chromosome with the duplication; in none of the nuclei analyzed was the order red-green-green-red or green-red-red-green, compatible with an inverted repeat. The authors suggested that those affected families in which there is no duplication of the PMP22 gene likely represent intragenic mutations comparable to those in the Trembler mouse. Hoogendijk et al. (1992) found the chromosome 17 duplication as a de novo mutation in 9 of 10 sporadic patients with HMSN I. During a population survey of CMT1 in south Wales, MacMillan et al. (1992) found duplication of locus D17S122, recognized by a DNA probe that detects an MspI polymorphism, in 10 of 11 families selected only by clinical criteria. Trisomy for this chromosome region is demonstrated either by the presence of 3 alleles or a dosage effect when only 2 of the alleles are present. The 1 family without trisomy did not differ in type or severity of disease from the other families. Lupski et al. (1992) described a patient with a cytogenetically visible duplication, dup(17)(p11.2p12). Molecular analysis demonstrated that this patient had duplications of all the DNA markers duplicated in other cases of CMT1A as well as of markers both proximal and distal to the CMT1A duplication. Upadhyaya et al. (1993) reported another instance of a microscopically visible duplication of 17p12-p11.2 in association with CMT1A. Wise et al. (1993) used 3 molecular methods to search for the CMT1A DNA duplication in 75 unrelated patients diagnosed clinically with CMT and evaluated by electrophysiologic methods. The CMT1A duplication was found in 68% of the 63 unrelated CMT patients with electrophysiologic studies consistent with CMT type 1. The CMT1A duplication was detected as a de novo event in 2 CMT1 families. Twelve CMT patients who did not have decreased nerve conduction velocities consistent with a diagnosis of CMT type 2 were found not to have the CMT1A duplication. The most informative molecular method was the detection of the CMT1A duplication-specific junction fragment by pulsed field gel electrophoresis. Given the high frequency of the CMT1A duplication in CMT patients and the high frequency of new mutations, Wise et al. (1993) concluded that a molecular test for the CMT1A DNA duplication is useful in the differential diagnosis of patients with peripheral neuropathies. In a 2-year-old boy with severe demyelinating CMT, Meggouh et al. (2005) identified compound heterozygosity for 2 mutations: the PMP22 duplication and a mutation in the LITAF gene (G112S; 603795.0001), which causes CMT1C (601098). Each parent was heterozygous for 1 of the mutations, and each had pes cavus and reduced nerve conduction velocities consistent with mild CMT. Meggouh et al. (2005) concluded that the cooccurrence of both mutations resulted in the more severe phenotype in the proband. In 3 members of a 4-generation family with Roussy-Levy syndrome (180800), Auer-Grumbach et al. (1998) identified the CMT1A PMP22 duplication. Miltenberger-Miltenyi et al. (2009) identified the CMT1A PMP22 1.4-Mb duplication in 79 (31.6%) of 250 unrelated Austrian patients with CMT. (less)
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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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Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2015 | PMID: 20301384 |
Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations. | Miltenberger-Miltenyi G | European journal of human genetics : EJHG | 2009 | PMID: 19259128 |
Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. | Meggouh F | Annals of neurology | 2005 | PMID: 15786462 |
Roussy-Lévy syndrome is a phenotypic variant of Charcot-Marie-Tooth syndrome IA associated with a duplication on chromosome 17p11.2. | Auer-Grumbach M | Journal of the neurological sciences | 1998 | PMID: 9543325 |
Charcot-Marie-tooth disease 1A (CMT1A) associated with a maternal duplication of chromosome 17p11.2-->12. | Upadhyaya M | Human genetics | 1993 | PMID: 8500795 |
Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication. | Wise CA | American journal of human genetics | 1993 | PMID: 8105684 |
Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). HMSN Collaborative Research Group. | Raeymaekers P | Journal of medical genetics | 1992 | PMID: 1552545 |
Charcot-Marie-Tooth disease type 1a (CMT1a): evidence for trisomy of the region p11.2 of chromosome 17 in south Wales families. | MacMillan JC | Journal of medical genetics | 1992 | PMID: 1552536 |
De-novo mutation in hereditary motor and sensory neuropathy type I. | Hoogendijk JE | Lancet (London, England) | 1992 | PMID: 1349106 |
The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. | Valentijn LJ | Nature genetics | 1992 | PMID: 1303229 |
Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. | Lupski JR | Nature genetics | 1992 | PMID: 1301995 |
Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. | Raeymaekers P | Neuromuscular disorders : NMD | 1991 | PMID: 1822787 |
The duplication in Charcot-Marie-Tooth disease type 1a spans at least 1100 kb on chromosome 17p11.2. | Hoogendijk JE | Human genetics | 1991 | PMID: 1721895 |
DNA duplication associated with Charcot-Marie-Tooth disease type 1A. | Lupski JR | Cell | 1991 | PMID: 1677316 |
Homozygous expression of a dominant gene for Charcot-Marie-Tooth neuropathy. | Killian JM | Annals of neurology | 1979 | PMID: 475348 |
THE BAR "GENE" A DUPLICATION. | Bridges CB | Science (New York, N.Y.) | 1936 | PMID: 17796454 |
Lupski, J. R., Garcia, C. A., Parry, G. J., Patel, P. I. Charcot-Marie-Tooth polyneuropathy syndrome: clinical, electrophysiological, and genetic aspects. In: Appel, S. Current Neurology. Chicago: Mosby-Yearbook (pub.) 1-25, 1991. | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated Jun 10, 2023
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.
NCBI staff provided an HGVS expression for allelic variant 601097.0001 based on the location of the forward primers for D17S2220 and D17S2230.