VCV000008428.8 - ClinVar

NM_000304.4(PMP22):c.47T>C (p.Leu16Pro)

Germline

Classification

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.

(3)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000304.4(PMP22):c.47T>C (p.Leu16Pro)

Variation ID: 8428 Accession: VCV000008428.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p12 17: 15260681 (GRCh38) [ NCBI UCSC ] 17: 15163998 (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	Feb 14, 2024	Jul 11, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_000304.4:c.47T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000295.1:p.Leu16Pro	missense
NM_001281455.2:c.47T>C	NP_001268384.1:p.Leu16Pro	missense
NM_001281456.2:c.47T>C	NP_001268385.1:p.Leu16Pro	missense
NM_001330143.2:c.47T>C	NP_001317072.1:p.Leu16Pro	missense
NM_153321.3:c.47T>C	NP_696996.1:p.Leu16Pro	missense
NM_153322.3:c.47T>C	NP_696997.1:p.Leu16Pro	missense
NC_000017.11:g.15260681A>G
NC_000017.10:g.15163998A>G
NG_007949.1:g.9647T>C
LRG_263:g.9647T>C
LRG_263t1:c.47T>C
	Q01453:p.Leu16Pro

... more HGVS ... less HGVS

Protein change

L16P

Other names

Canonical SPDI

NC_000017.11:15260680:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA340784 UniProtKB: Q01453#VAR_006360 OMIM: 601097.0002 dbSNP: rs104894617 VarSome

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
Gene	OMIM	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.
PMP22		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	409	527

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.
Charcot-Marie-Tooth disease, type IA	Pathogenic (2)	no assertion criteria provided	May 1, 1993	RCV000008940.7
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Jul 11, 2019	RCV000685070.6

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.
Pathogenic (Jul 11, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease, type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000812542.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 28492532‚ 8995589‚ 1303281‚ 23689413‚ 26102530‚ 18795802‚ 21827951‚ 25385046‚ 9425015‚ 6313869‚ 12090404 Comment: This variant has been reported to be de novo in an individual affected with¬†Charcot-Marie-Tooth disease, type 1 (CMT1) (PMID: 8995589) and has been reported to … (more) This variant has been reported to be de novo in an individual affected with¬†Charcot-Marie-Tooth disease, type 1 (CMT1) (PMID: 8995589) and has been reported to segregate with CMT1 in affected families (PMID: 8995589, 1303281). It has also been reported in an unrelated individual affected with CMT1 (PMID: 23689413). ClinVar contains an entry for this variant (Variation ID: 8428). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 16 of the PMP22 protein (p.Leu16Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. Experimental studies have shown that this missense change results in an unstable, improperly folded and mislocalized protein (PMID: 26102530, 18795802, 21827951, 25385046, 9425015). Furthermore, mouse models with this missense change recapitulate the human phenotype (PMID: 6313869, 12090404). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 1993)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, TYPE 1A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029150.4 First in ClinVar: Apr 04, 2013 Last updated: May 19, 2019	Publications: PubMed (3) PubMed: 1303281‚ 8492918‚ 1564512 Comment on evidence: Valentijn et al. (1992) demonstrated a mutation leading to the substitution of proline for leucine in the first putative transmembrane domain of PMP22 as the … (more) Valentijn et al. (1992) demonstrated a mutation leading to the substitution of proline for leucine in the first putative transmembrane domain of PMP22 as the cause of Charcot-Marie-Tooth disease type 1A (CMT1A; 118220) in a Dutch kindred. A T-to-C transition at position 96 was responsible for the leu16-to-pro (L16P) substitution. The identical mutation had been identified in the 'Trembler-J' mouse, a homolog of the human disease. Thus, either duplication or point mutation in the PMP22 gene can result in CMT1A. Hoogendijk et al. (1993) had previously shown that the clinical disorder in this family was tightly linked to a probe on 17p11.2. The histopathologic abnormalities in nerve biopsies of patients from this family were unusually severe (Gabreels-Festen et al., 1992). Hoogendijk et al. (1993) commented that, according to the clinical, neurophysiologic, and morphologic criteria used by some investigators, most of the patients in this family would individually be given a diagnosis of hereditary motor and sensory neuropathy type III (HMSN3; 145900). (less)
not provided (-)	no classification provided Method: literature only	Charcot-Marie-Tooth disease, type IA Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000055666.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301384 BookShelf: NBK1205 BookShelf: NBK1205

Comment:

This variant has been reported to be de novo in an individual affected with¬†Charcot-Marie-Tooth disease, type 1 (CMT1) (PMID: 8995589) and has been reported to segregate with CMT1 in affected families (PMID: 8995589, 1303281). It has also been reported in an unrelated individual affected with CMT1 (PMID: 23689413). ClinVar contains an entry for this variant (Variation ID: 8428). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 16 of the PMP22 protein (p.Leu16Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. Experimental studies have shown that this missense change results in an unstable, improperly folded and mislocalized protein (PMID: 26102530, 18795802, 21827951, 25385046, 9425015). Furthermore, mouse models with this missense change recapitulate the human phenotype (PMID: 6313869, 12090404). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22.	Schlebach JP	Journal of the American Chemical Society	2015	PMID: 26102530
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2015	PMID: 20301384
Rer1 and calnexin regulate endoplasmic reticulum retention of a peripheral myelin protein 22 mutant that causes type 1A Charcot-Marie-Tooth disease.	Hara T	Scientific reports	2014	PMID: 25385046
Proptosis in a family with the p16 Leuc-to-Prol mutation in the PMP22 gene (CMT 1E).	Calia L	Arquivos de neuro-psiquiatria	2013	PMID: 23689413
Structural basis for the Trembler-J phenotype of Charcot-Marie-Tooth disease.	Sakakura M	Structure (London, England : 1993)	2011	PMID: 21827951
The peripheral neuropathy-linked Trembler and Trembler-J mutant forms of peripheral myelin protein 22 are folding-destabilized.	Myers JK	Biochemistry	2008	PMID: 18795802
Comparison of a new pmp22 transgenic mouse line with other mouse models and human patients with CMT1A.	Robertson AM	Journal of anatomy	2002	PMID: 12090404
Overloaded endoplasmic reticulum-Golgi compartments, a possible pathomechanism of peripheral neuropathies caused by mutations of the peripheral myelin protein PMP22.	D'Urso D	The Journal of neuroscience : the official journal of the Society for Neuroscience	1998	PMID: 9425015
Dejerine-Sottas neuropathy in mother and son with same point mutation of PMP22 gene.	Ionasescu VV	Muscle & nerve	1997	PMID: 8995589
Allelic heterogeneity in hereditary motor and sensory neuropathy type Ia (Charcot-Marie-Tooth disease type 1a).	Hoogendijk JE	Neurology	1993	PMID: 8492918
Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I).	Gabreëls-Festen AA	Journal of the neurological sciences	1992	PMID: 1564512
Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A.	Valentijn LJ	Nature genetics	1992	PMID: 1303281
Comparison of Trembler and Trembler-J mouse phenotypes: varying severity of peripheral hypomyelination.	Henry EW	Journal of neuropathology and experimental neurology	1983	PMID: 6313869
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Text-mined citations for rs104894617 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000304.4(PMP22):c.47T>C (p.Leu16Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894617 ...