GeneBe

LMBRD1

protein-coding

LMBR1 domain containing 1

Gene summary

This gene encodes a lysosomal membrane protein that may be involved in the transport and metabolism of cobalamin. This protein also interacts with the large form of the hepatitis delta antigen and may be required for the nucleocytoplasmic shuttling of the hepatitis delta virus. Mutations in this gene are associated with the vitamin B12 metabolism disorder termed, homocystinuria-megaloblastic anemia complementation type F.[provided by RefSeq, Oct 2009]

Previous symbols:
  • C6orf209

MANE transcript

NM_018368.4

Inheritance

AR

ClinVar variants

P:61U:153B:123

Top phenotype

Methylmalonic aciduria and homocystinuria, cblF type

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr6:69,672,757-69,867,236

External References & Databases

Ensembl (ENSG00000168216)NCBI Gene (55788)OMIM (612625)HGNC:23038GenCCUniProt (Q9NUN5)AlphaFoldClinVar (LMBRD1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~194.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylmalonic aciduria and homocystinuria type cblFDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010183

Submitter: ClinGen

LMBRD1 was first reported in relation to autosomal recessive inheritance of methylmalonic aciduria and homocystinuria type cblF in 2009 (Rutsch F, et al. PMID: 19136951). At least 10 unique loss of function variants (including nonsense, frameshift, and splicing) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 19136951, 32875039, 20127417, 21303734). This gene-disease relationship is supported by experimental evidence of the biochemical function in transport of ABCD4 for delivery of lysosomal vitamin B(12) to cytoplasmic MMACHC, consistent with the elevated methylmalonic acid and homocysteine phenotypes (PMID: 27456980), and rescue of the biochemical cblF phenotype in patient cells transfected with a wild-type construct (PMID: 19136951). In summary, LMBRD1 is definitively associated with autosomal recessive inheritance of methylmalonic aciduria and homocystinuria type cblF.

methylmalonic aciduria and homocystinuria type cblFDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010183

Submitter: G2P

methylmalonic aciduria and homocystinuria type cblFSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010183

Submitter: PanelApp Australia

methylmalonic aciduria and homocystinuria type cblFSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010183

Submitter: Orphanet

methylmalonic aciduria and homocystinuria type cblFSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010183

Submitter: Labcorp Genetics (formerly Invitae)

methylmalonic aciduria and homocystinuria type cblFSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010183

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Methylmalonic aciduria and homocystinuria, cblF typeAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Dermatologic; Hematologic; Neurologic

Intervention: Biochemical

Rationale: While no treatment is completely effective, specific dietary (eg, high-calorie, low protein diet and avoidance of fasting, with measures taken to avoid/treat decompensation) and other medical measures (eg, cofactor therapy with hydroxycobalamin) may be beneficial to treat and prevent sequelae in the acute and chronic states

Refs: 4001945; 3725502; 20301503; 19136951; 20127417; 21910240; 21303734; 22065268; 20446115Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LMBRD1 variants in ClinVar

8 Conditions Cataloged
Methylmalonic aciduria and homocystinuria type cblFTotal: 423
Inborn genetic diseasesTotal: 82
not providedTotal: 48
not specifiedTotal: 23
LMBRD1-related disorderTotal: 8
Cobalamin C diseaseTotal: 7
Disorders of Intracellular Cobalamin MetabolismTotal: 1
Donnai-Barrow syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018368.4. 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.

EffectPLPVUSLBBSum
synonymous
118
clinvar
1
clinvar
 119
missense
153
clinvar
4
clinvar
 157
nonsense
10
clinvar
5
clinvar
 15
start loss
1
clinvar
 1
frameshift
15
clinvar
7
clinvar
 22
splice donor/acceptor (+/-2bp)
1
clinvar
22
clinvar
 23
Total26351531221337

Highest pathogenic variant AF is 0.0006095659

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_018368.4RefSeqNP_060838.316MANE Select
ENST00000649934.3EnsemblENSP00000497690.116MANE Select
NM_001363722.2RefSeqNP_001350651.115Standard
NM_001367271.1RefSeqNP_001354200.115Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Vitamin digestion and absorption - Homo sapiens (human)
  • Cobalamin (Cbl, vitamin B12) transport and metabolism
  • Metabolism
  • Metabolism of water-soluble vitamins and cofactors
  • Metabolism of vitamins and cofactors

Biological Process

  • cobalamin metabolic process
  • cobalamin transport
  • viral process

Molecular Function

  • insulin receptor binding
  • cobalamin-transporting ATPase activity
  • cobalamin binding

Cellular Component

  • lysosomal membrane
  • plasma membrane
  • membrane
  • integral component of membrane
  • clathrin-coated endocytic vesicle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000370577
Coding exons
16
Length
121310
Individuals with no LoFs
125553
Homozygous LoFs
0
Heterozygous LoFs
195
Defined
125748
p
0.000776
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2572722840.9570.00001423512
Missense (PolyPhen)5871.0690.8161859
Synonymous0.5599198.00.9280.000004861005
Loss of Function1.882132.60.6440.00000164406

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00140.0014notable
Latino/Admixed American0.000440.00043rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.000740.00074rare
European (Non-Finnish)0.00120.0011notable
South Asian0.000200.00020rare
Other0.000660.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Probable lysosomal cobalamin transporter. Required to export cobalamin from lysosomes allowing its conversion to cofactors. {ECO:0000269|PubMed:19136951}.;
Disease
DISEASE: Methylmalonic aciduria and homocystinuria, cblF type (MAHCF) [MIM:277380]: An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). It is due to accumulation of free cobalamin in lysosomes, thus hindering its conversion to cofactors. Clinical features include developmental delay, stomatitis, glossitis, seizures and methylmalonic aciduria responsive to vitamin B12. {ECO:0000269|PubMed:19136951}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.103

Intolerance Scores

LoFtool
0.919
RVIS EVS
-0.56
RVIS percentile EVS
19.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.132

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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