PREPL

protein-coding

prolyl endopeptidase like

Gene summary

The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

MANE transcript

NM_001171613.2

Inheritance

ClinVar variants

P:56U:310B:172

Top phenotype

Myasthenic syndrome, congenital 22

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr2:44,316,281-44,361,862

External References & Databases

Ensembl (ENSG00000138078)

Transcript & Mutation Effects

hg38 • Region Span ~45.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myasthenic syndrome, congenital, 22MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044299

Submitter: Ambry Genetics

myasthenic syndrome, congenital, 22MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044299

Submitter: Illumina

The PREPL gene is located on chromosome 2 at 2p21 and encodes the prolyl endopeptidase like protein, which encodes a putative serine peptidase from the prolyl oligopeptidase family. The protein is ubiquitously expressed with higher levels found in the brain, kidney, and muscle, however, the biological role of the PREPL is yet to be fully elucidated. PREPL was first reported in relation to autosomal recessive isolated PREPL-related myasthenic syndrome, congenital in 2018 (28726805: Regal et al. 2018). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least six unique variants including deletion, frameshift, and splice variants have been reported in four probands from three publications (28726805: Regal et al. 2018; 29483676: Silva et al. 2018; 29913539: Laugwitz et al. 2018). All variants were found in either a homozygous state or a compound heterozygous state with a second deleterious variant. This gene-disease relationship is supported by expression studies that demonstrate colocalization of PREPL with alpha bungarotoxin within muscle fibers and at the endplates (24610330: Regal et al. 2014) and Prepl knockout mice that recapitulate the key features of the disorder including stunted growth and neonatel hypotonia which resolves over time (24586561: Lone et al. 2014). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

myasthenic syndrome, congenital, 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044299

Submitter: PanelApp Australia

hypotonia-cystinuria syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011669

Submitter: G2P

myasthenic syndrome, congenital, 22STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044299

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital 22AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Medical treatment with acetylcholine esterase inhibitors has been described as beneficial in one individual; In infancy, the use of apnea monitors may be indicated; Agents that affect neuromuscular transmission and exacerbate myasthenic manifestations should be avoided

Refs: 24610330

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PREPL variants in ClinVar

7 Conditions Cataloged

Myasthenic syndrome, congenital, 22Total: 651

Inborn genetic diseasesTotal: 136

not providedTotal: 69

PREPL-related disorderTotal: 37

not specifiedTotal: 24

Premature ovarian insufficiencyTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001171613.2. 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			2 clinvar	151 clinvar	4 clinvar	157
missense		1 clinvar	303 clinvar	16 clinvar	1 clinvar	321
nonsense	13 clinvar	5 clinvar	1 clinvar			19
start loss			1 clinvar			1
frameshift	15 clinvar	6 clinvar				21
splice donor/acceptor (+/-2bp)	1 clinvar	15 clinvar	3 clinvar			19
Total	29	27	310	167	5	538

Highest pathogenic variant AF is 0.00024181338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001171613.2	RefSeq	NP_001165084.1	13	MANE Select
ENST00000409411.6	Ensembl	ENSP00000387095.2	13	MANE Select
NM_001042385.2	RefSeq	NP_001035844.1	13	Standard
NM_001042386.2	RefSeq	NP_001035845.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

proteolysis
regulation of synaptic vesicle exocytosis

Molecular Function

serine-type endopeptidase activity
protein binding
serine-type exopeptidase activity

Cellular Component

Golgi apparatus
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409936
Coding exons: 14
Length: 45582
Individuals with no LoFs: 125620
Homozygous LoFs: 0
Heterozygous LoFs: 128
Defined: 125748
p: 0.000509

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.50	539	399	1.35	0.0000211	4833
Missense (PolyPhen)		143	112.27	1.2738		1333
Synonymous	-2.23	174	140	1.24	0.00000766	1308
Loss of Function	1.58	25	35.1	0.712	0.00000170	467

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00094	0.00093	rare
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.00082	0.00076	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00066	0.00065	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable serine peptidase whose precise substrate specificity remains unclear. Does not cleave peptides after a arginine or lysine residue. May play a role in the regulation of synaptic vesiscle exocytosis (PubMed:24610330). {ECO:0000269|PubMed:16143824, ECO:0000269|PubMed:16385448, ECO:0000269|PubMed:24610330}.;
Disease: DISEASE: Myasthenic syndrome, congenital, 22 (CMS22) [MIM:616224]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features include easy fatigability and muscle weakness. CMS22 is an autosomal recessive form characterized by neonatal hypotonia. {ECO:0000269|PubMed:24610330}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.0602
RVIS EVS: -0.84
RVIS percentile EVS: 11.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.944

Gene Damage Prediction

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