LMBRD1

Chr 6AR

LMBR1 domain containing 1

Also known as: C6orf209, LMBD1, MAHCF, NESI

NCBI Gene: 55788 ENSG00000168216 UniProt: Q9NUN5 OMIM: 277380

The LMBRD1 protein functions as a lysosomal membrane chaperone that exports cobalamin (vitamin B12) from lysosomes to the cytosol by forming a complex with ABCD4 and MMACHC transporters. Mutations cause methylmalonic aciduria and homocystinuria (cblF and cblJ types), disorders of vitamin B12 metabolism that typically present in infancy with developmental delay, failure to thrive, and megaloblastic anemia. This condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.933 OMIM phenotypes

Clinical Summary— LMBRD1

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Gene-Disease Validity (ClinGen)

methylmalonic aciduria and homocystinuria type cblF · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

60 unique Pathogenic / Likely Pathogenic· 160 VUS of 559 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LMBRD1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.88

OE 0.64 (0.46–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.26Z-score

OE missense 0.96 (0.87–1.06)

272 obs / 284.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.46–0.93)

0≤0.351.4

Missense OE?0.96 (0.87–1.06)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 21 / 32.6Missense obs/exp: 272 / 284.2Syn Z: 0.56

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveLMBRD1-related methylmalonic aciduria and homocystinuriaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6357th %ile

GOF

0.7028th %ile

LOF

0.2970th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

559 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28

Likely Pathogenic32

VUS160

Likely Benign276

Benign43

Conflicting9

Pathogenic

Likely Pathogenic

160

VUS

276

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	0	4	0	28
Likely Pathogenic	31	1	0	0	32
VUS	0	145	15	0	160
Likely Benign	0	3	162	111	276
Benign	0	1	40	2	43
Conflicting	—				9
Total	55	150	221	113	548

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap LMBRD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →