PMP2

protein-coding

peripheral myelin protein 2, the group of Fatty acid binding protein family

Gene summary

The protein encoded by this gene localizes to myelin sheaths of the peripheral nervous system. The encoded protein can bind both the membrane layers of the sheaths and monomeric lipids, and is thought to provide stability to the sheath. A defect in this gene was shown to be a cause of dominant demyelinating CMT neuropathy. [provided by RefSeq, Jan 2017]

MANE transcript

NM_002677.5

Inheritance

ClinVar variants

P:7U:66B:25

Top phenotype

Charcot-Marie-Tooth disease, demyelinating, type 1G

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr8:81,440,326-81,447,439

External References & Databases

Ensembl (ENSG00000147588)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease, demyelinating, type 1GMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033135

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease, demyelinating, type 1GSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033135

Submitter: Orphanet

Charcot-Marie-Tooth diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015626

Submitter: ClinGen

PMP2 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2015 (Gonzaga-Jauregui et al., PMID: 26257172). At least six variants (e.g. missense, in-frame indel) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, limited segregation data, and experimental data. Variants in this gene have been reported in at least nine probands in seven publications (PMIDs: 26257172, 27009151, 30249361, 31412900, 26828946, 32277537, 37238449). Variants in this gene segregated with disease in several additional family members, including a large multi-generational family (37238449). There is variant level experimental evidence to support pathogenicity of 6 of the reported variants (PMID: 28747762, 34138518). In total, genetic evidence totals 4.5 points. The mechanism for disease is suspected to be a monoallelic gain-of-function or dominant negative effect with variants affecting the myelin structure or causing upregulation of the protein (PMID: 28747762). This gene-disease association is additionally supported by PMP2's function in lipid homeostasis and remyelination, as well as functional evidence in PMP2 null mice. Expression of PMP2 in myelin, interacting with MPZ, a protein also associated with demyelinating CMT, also provides evidence towards its pathogenicity. A transgenic mouse model expressing the I43N variant does recapitulate many of the phenotypes observed in humans. However, the possibility for interference via overexpression, rather than from the variant itself, requires more clarification in future studies. In total, experimental evidence totals 2.5. In summary, there is moderate evidence to support this gene-disease relationship with a total of 7 points. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Charcot-Marie-Tooth disease, demyelinating, type 1GSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033135

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease, demyelinating, type 1GMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033135

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, demyelinating, type 1GAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26257172; 26828946; 27009151; 30249361

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PMP2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 113

Inborn genetic diseasesTotal: 16

Charcot-Marie-Tooth disease, demyelinating, type 1GTotal: 13

not specifiedTotal: 11

PMP2-related disorderTotal: 6

Peripheral neuropathyTotal: 2

Charcot-Marie-Tooth disease type 1ETotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002677.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	15 clinvar		18
missense	1 clinvar	6 clinvar	55 clinvar	6 clinvar	4 clinvar	72
nonsense			3 clinvar			3
start loss			1 clinvar			1
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	1	6	66	21	4	98

Highest pathogenic variant AF is 6.8421355e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002677.5	RefSeq	NP_002668.1	4	MANE Select
ENST00000256103.3	Ensembl	ENSP00000256103.2	4	MANE Select
NM_001348381.2	RefSeq	NP_001335310.1	3	Standard
ENST00000519260.1	Ensembl	ENSP00000429917.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glucocorticoid Receptor Pathway
Nuclear Receptors Meta-Pathway

Biological Process

membrane organization

Molecular Function

fatty acid binding
protein binding
cholesterol binding

Cellular Component

cytoplasm
myelin sheath
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000256103
Coding exons: 4
Length: 7198
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125730
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0996	67	69.3	0.966	0.00000334	863
Missense (PolyPhen)		17	17.503	0.97127		247
Synonymous	0.554	22	25.6	0.861	0.00000135	241
Loss of Function	1.05	4	6.99	0.572	3.93e-7	82

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0.000036	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in lipid transport protein in Schwann cells. May bind cholesterol. {ECO:0000269|PubMed:20421974}.;

Recessive Scores

pRec: 0.364

Intolerance Scores

LoFtool: 0.585
RVIS EVS: 0.55
RVIS percentile EVS: 81.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.262

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium