UBR1

protein-coding

ubiquitin protein ligase E3 component n-recognin 1, the group of Ubiquitin protein ligase E3 component n-recognins

Gene summary

The N-end rule pathway is one proteolytic pathway of the ubiquitin system. The recognition component of this pathway, encoded by this gene, binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain. This leads to the eventual degradation of the substrate protein. The protein described in this record has a RING-type zinc finger and a UBR-type zinc finger. Mutations in this gene have been associated with Johanson-Blizzard syndrome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_174916.3

Inheritance

ClinVar variants

P:72U:244B:441

Top phenotype

Johanson-Blizzard syndrome

gnomAD constraint

pLI —, LoF o/e 0.25

Max pathogenic AF

—

Genomic locus

chr15:42,942,897-43,106,113

External References & Databases

Ensembl (ENSG00000159459)

Transcript & Mutation Effects

hg38 • Region Span ~163.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Johanson-Blizzard syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009479

Submitter: PanelApp Australia

Johanson-Blizzard syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009479

Submitter: Labcorp Genetics (formerly Invitae)

Johanson-Blizzard syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009479

Submitter: ClinGen

*UBR1* (Ubiquitin-Protein Ligase E3 Component N-Recognin 1) is located on chromosome 15q15.2 and codes for ubiquitin protein ligase E3 component n-recognin 1 protein, the recognition component of the N-end rule proteolytic pathway of the ubiquitin system, helping form a substrate-associated multiubiquitin chain. *UBR1* was first reported in relation to autosomal recessive Johanson-Blizzard Syndrome (JBS) in 2005 (Zenker et al., PMID: 16311597). This condition is characterized by pancreatic insufficiency, nasal anomalies, oligodontia, hearing impairment, cognitive impairment, and short stature. 15 variants (missense, nonsense, frameshift, & splicing) that have been reported in over 20 probands in 4 publications (PMIDs: 16311597, 18553553, 19006206, 24599544) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (a mouse model, biochemical functional evidence and functional alteration in non-patient cells; PMIDs: 16311597, 33554225, 21931868). Homozygous mutant mice show growth delay, reduced body weight, pancreatic issues, and reductions in muscle and adipose tissue. Biochemical functional and functional alteration evidence in yeast supports that the protein is necessary in protein quality regulation, and by extension, indicates that JBS may be fully or partially due to deficiency of protein quality control triggered by *UBR1* loss-of-function. In summary, there is definitive evidence supporting the relationship between *UBR1* and autosomal recessive JBS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 7/22/2025 (SOP Version 11).

Johanson-Blizzard syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009479

Submitter: G2P

Johanson-Blizzard syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009479

Submitter: Orphanet

Clinical Genomic Database (CGD)

Johanson-Blizzard syndromeAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Dermatologic; Cardiovascular; Endocrine; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Gastrointestinal; Hematologic

Rationale: Medical treatment of exocrine pancreatic insufficiency can be beneficial; Awareness of cardiovascular manifestastions (which can include structural malformations as well as cardiomyopathy) can allow early diagnosis and treatment; As the condition can include congenital deafness, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Treatment of endocrine manifestations, such as hypothyroidism, growth hormone deficiency, and diabetes mellitus, can be beneficial; Severe anemia requiring transfusions has been described, and awareness may allow prompt diagnosis and treatment

Refs: 5171616; 728568; 474625; 4050852; 2645405; 12535044; 12725595; 14647752; 15379429; 16311597; 16632090; 17378628; 18553553; 19058315; 19006206; 19717322; 20556423; 21931868; 20556422; 21429315; 21711208; 22072859; 23463671; 23778732; 24052374

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBR1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 958

Inborn genetic diseasesTotal: 178

Johanson-Blizzard syndromeTotal: 42

UBR1-related disorderTotal: 36

not specifiedTotal: 22

MicrocephalyTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_174916.3. 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	370 clinvar	20 clinvar	393
missense		8 clinvar	230 clinvar	47 clinvar	4 clinvar	289
nonsense	18 clinvar	2 clinvar	1 clinvar			21
start loss						0
frameshift	14 clinvar	7 clinvar				21
splice donor/acceptor (+/-2bp)	4 clinvar	19 clinvar	10 clinvar			33
Total	36	36	244	417	24	757

Highest pathogenic variant AF is 0.00005763367

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_174916.3	RefSeq	NP_777576.1	47	MANE Select
ENST00000290650.9	Ensembl	ENSP00000290650.4	47	MANE Select
ENST00000546274.6	Ensembl	ENSP00000477932.1	29	Standard
ENST00000546274.7	Ensembl	ENSP00000477932.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

protein ubiquitylation
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation

Biological Process

protein ubiquitination
negative regulation of TOR signaling
cellular response to leucine
ubiquitin-dependent protein catabolic process via the N-end rule pathway

Molecular Function

protein binding
zinc ion binding
ubiquitin protein ligase activity
leucine binding

Cellular Component

ubiquitin ligase complex
proteasome complex
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290650
Coding exons: 47
Length: 163217
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.40	714	918	0.777	0.0000463	11593
Missense (PolyPhen)		146	279.14	0.52303		3529
Synonymous	-0.546	319	307	1.04	0.0000155	3135
Loss of Function	7.15	27	107	0.253	0.00000531	1329

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. May be involved in pancreatic homeostasis. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth. {ECO:0000269|PubMed:15548684, ECO:0000269|PubMed:16311597, ECO:0000269|PubMed:20298436, ECO:0000269|PubMed:20835242}.;
Disease: DISEASE: Johanson-Blizzard syndrome (JBS) [MIM:243800]: This disorder includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. Pancreas of individuals with JBS do not express UBR1 and show intrauterine-onset destructive pancreatitis. {ECO:0000269|PubMed:16311597, ECO:0000269|PubMed:21931868, ECO:0000269|PubMed:22072859, ECO:0000269|PubMed:24599544, ECO:0000269|PubMed:26149651}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.194

Intolerance Scores

LoFtool: 0.598
RVIS EVS: -0.63
RVIS percentile EVS: 16.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.775

Gene Damage Prediction

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