LMBR1

Summary

LMBR1 (limb development membrane protein 1, HGNC:13243) is a protein-coding gene on chromosome 7q36.3, encoding Limb region 1 protein homolog (Q8WVP7). Putative membrane receptor.

This gene encodes a member of the LMBR1-like membrane protein family. Another member of this protein family has been shown to be a lipocalin transmembrane receptor. A highly conserved, cis-acting regulatory module for the sonic hedgehog gene is located within an intron of this gene. Consequently, disruption of this genic region can alter sonic hedgehog expression and affect limb patterning, but it is not known if this gene functions directly in limb development. Mutations and chromosomal deletions and rearrangements in this genic region are associated with acheiropody and preaxial polydactyly, which likely result from altered sonic hedgehog expression.

Source: NCBI Gene 64327 — RefSeq curated summary.

At a glance

• Gene–disease (curated): polydactyly of a triphalangeal thumb (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 579 total — 20 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 75
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022458

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13243
Approved symbol	LMBR1
Name	limb development membrane protein 1
Location	7q36.3
Locus type	gene with protein product
Status	Approved
Aliases	ACHP, FLJ11665, ZRS
Ensembl gene	ENSG00000105983
Ensembl biotype	protein_coding
OMIM	605522
Entrez	64327

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 21 protein_coding, 8 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay, 3 retained_intron

ENST00000353442, ENST00000414218, ENST00000415428, ENST00000430278, ENST00000430825, ENST00000433968, ENST00000434278, ENST00000434453, ENST00000434503, ENST00000444719, ENST00000448926, ENST00000454132, ENST00000461469, ENST00000461603, ENST00000477983, ENST00000485985, ENST00000486837, ENST00000498034, ENST00000609081, ENST00000609774, ENST00000875396, ENST00000875397, ENST00000875398, ENST00000875399, ENST00000875400, ENST00000875401, ENST00000875402, ENST00000875403, ENST00000875404, ENST00000875405, ENST00000931565, ENST00000931566, ENST00000931567, ENST00000956573, ENST00000956574, ENST00000956575, ENST00000956576, ENST00000956577, ENST00000956578

RefSeq mRNA: 12 — MANE Select: NM_022458 NM_001350953, NM_001350954, NM_001350955, NM_001350956, NM_001350957, NM_001350958, NM_001363409, NM_001363410, NM_001363411, NM_001363412, NM_001363413, NM_022458

CCDS: CCDS5945

Canonical transcript exons

ENST00000353442 — 17 exons

Exon	Start	End
ENSE00001425028	156677791	156684163
ENSE00001936388	156892928	156893183
ENSE00003472782	156725435	156725525
ENSE00003512660	156734177	156734257
ENSE00003538072	156727930	156728007
ENSE00003565477	156725764	156725837
ENSE00003576926	156826605	156826744
ENSE00003612692	156756393	156756465
ENSE00003613782	156833753	156833792
ENSE00003623338	156728644	156728720
ENSE00003641265	156688030	156688191
ENSE00003663068	156796389	156796492
ENSE00003663859	156724112	156724178
ENSE00003664818	156763669	156763795
ENSE00003673190	156836813	156836885
ENSE00003674708	156762134	156762198
ENSE00003684652	156763108	156763176

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 97.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.9789 / max 4655.8155, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87058	41.0206	1822
87059	3.2241	1344
87054	0.9976	108
205019	0.7366	383

Top tissues by expression

252 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	97.50	gold quality
sural nerve	UBERON:0015488	96.72	gold quality
calcaneal tendon	UBERON:0003701	94.78	gold quality
bone marrow cell	CL:0002092	93.56	gold quality
right adrenal gland cortex	UBERON:0035827	92.67	gold quality
cortical plate	UBERON:0005343	92.14	gold quality
left adrenal gland	UBERON:0001234	91.90	gold quality
adrenal gland	UBERON:0002369	91.90	gold quality
right adrenal gland	UBERON:0001233	91.74	gold quality
left adrenal gland cortex	UBERON:0035825	91.70	gold quality
colonic epithelium	UBERON:0000397	90.71	gold quality
ganglionic eminence	UBERON:0004023	90.65	gold quality
adrenal cortex	UBERON:0001235	90.61	gold quality
islet of Langerhans	UBERON:0000006	90.49	gold quality
smooth muscle tissue	UBERON:0001135	90.25	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.10	gold quality
ventricular zone	UBERON:0003053	89.67	gold quality
prefrontal cortex	UBERON:0000451	89.32	gold quality
secondary oocyte	CL:0000655	88.51	gold quality
corpus epididymis	UBERON:0004359	88.37	gold quality
gall bladder	UBERON:0002110	88.08	gold quality
monocyte	CL:0000576	87.63	gold quality
leukocyte	CL:0000738	87.42	gold quality
tendon	UBERON:0000043	87.25	gold quality
stromal cell of endometrium	CL:0002255	87.13	gold quality
body of uterus	UBERON:0009853	86.96	gold quality
oocyte	CL:0000023	86.92	gold quality
rectum	UBERON:0001052	86.89	gold quality
left ovary	UBERON:0002119	86.62	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.52	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.38
E-MTAB-7606	no	1757.77
E-GEOD-75367	no	131.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

138 targeting LMBR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• mutation causes preaxial polydactyly (PMID:12032320)
• disruption is associated with preaxial polydactyly (PMID:12491086)
• C to T transition in LMBR1 results in the dysregulation of sonic hedgehog, which leads to the triphalangeal thumb-polysyndactyly syndrome found in this case (PMID:17300748)
• Intron 5 of LMBR1 was presumably subject to balancing selection during the evolution of modern human of various racial stocks. (PMID:18698406)
• Effect on transcription factor binding of a novel ZRS point mutation (463T>G) in a Pakistani family with preaxial polydactyly and triphalangeal thumb. (PMID:20068592)
• A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb. (PMID:22495965)
• report of a new point mutation within the ZRS in a family with digit malformations including triphalangeal thumb, pre-axial polydactyly and post-axial polydactyly; heterozygous C>A mutation at position 287 of the ZRS enhancer was detected in all affected subjects and is absent from four unaffected family members (PMID:22786669)
• Review of the literature and cases in a Chinese family confirm genetic homogeneity (duplication of ZRS wintin intron 5 of LMBR1) of syndactyly type IV and triphalangeal thumb-polysyndactyly syndrome. (PMID:23793141)
• Data describe extensive variation in limb phenotype in a large family and report on a novel sequence variation NG_009240.1: g.106737G>T (traditional nomenclature: ZRS404G>T) in the ZRS within the LMBR1 gene. (PMID:24478176)
• A novel ZRS mutation found in the Mexican population, 402C>T, suggests that a dosage effect exists for this mutation. (PMID:24777739)
• These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1 (PMID:26749485)
• Results identify a novel g.101779T>A variant segregating with all individuals affected with preaxial polydactyly type 1(PPDI). (PMID:31395945)
• Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes. (PMID:32179704)
• Large duplication in LMBR1 gene in a large Chinese pedigree with triphalangeal thumb polysyndactyly syndrome. (PMID:32662247)
• PAR1 Activation, via LMBR1/BMP Axis, Promotes the Osteogenesis of Periodontal Ligament Stem Cells (PDLSCs) and Alleviates the Inhibitory Effect of Sodium Butyrate on PDLSCs Osteogenesis. (PMID:39190381)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lmbr1	ENSDARG00000024092
mus_musculus	Lmbr1	ENSMUSG00000010721
rattus_norvegicus	Lmbr1	ENSRNOG00000059589
drosophila_melanogaster	lili	FBGN0027539
caenorhabditis_elegans		WBGENE00019877

Paralogs (1): LMBR1L (ENSG00000139636)

Protein

Protein identifiers

Limb region 1 protein homolog — Q8WVP7 (reviewed: Q8WVP7)

Alternative names: Differentiation-related gene 14 protein

All UniProt accessions (9): Q8WVP7, F2Z2Z3, F8WB14, F8WCL1, F8WDW0, F8WEK4, F8WEN8, H0Y6V6, H7C1Y4

UniProt curated annotations — full annotation on UniProt →

Function. Putative membrane receptor.

Subcellular location. Membrane.

Tissue specificity. Widely expressed with strongest expression in heart and pancreas.

Disease relevance. Preaxial polydactyly 2 (PPD2) [MIM:174500] Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations are located in intron 5 of LMBR1. The mutations do not alter normal LMBR1 expression and function, but disrupt a long-range, cis-regulatory element of SHH expression contained in LMBR1 intron 5, known as ZPA regulatory sequence (ZRS). Triphalangeal thumb with polysyndactyly (TPTPS) [MIM:190605] Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression. Acheiropody (ACHP) [MIM:200500] Very rare condition characterized by bilateral congenital amputations of the hands and feet. The specific malformative phenotype consists of a complete amputation of the distal epiphysis of the humerus, amputation of the tibial diaphysis and aplasia of the radius, ulna, fibula and of all the bones of the hands and feet. The disease is caused by variants affecting the gene represented in this entry. Syndactyly 4 (SDTY4) [MIM:186200] A form of syndactyly, a congenital anomaly of the hand or foot marked by persistence of the webbing between adjacent digits that are more or less completely attached. SDTY4 is characterized by complete bilateral syndactyly (involving all digits 1 to 5). A frequent association with polydactyly (with six metacarpals and six digits) has been reported. Feet are affected occasionally. The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations consists of duplications (89-589 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5. The mutations do not alter normal LMBR1 expression and function, but affect SHH limb expression. Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740] An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations are located in intron 5 of LMBR1. The mutations do not alter normal LMBR1 expression and function, but disrupt a long-range, cis-regulatory element of SHH expression contained in LMBR1 intron 5. Laurin-Sandrow syndrome (LSS) [MIM:135750] A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). The disease is caused by variants affecting the gene represented in this entry. Disease-causing mutations consists of duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5. The mutations do not alter normal LMBR1 expression and function, but affect SHH limb expression.

Similarity. Belongs to the LIMR family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WVP7-1	1	yes
Q8WVP7-2	2
Q8WVP7-3	3

RefSeq proteins (12): NP_001337882, NP_001337883, NP_001337884, NP_001337885, NP_001337886, NP_001337887, NP_001350338, NP_001350339, NP_001350340, NP_001350341, NP_001350342, NP_071903* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006876	LMBR1-like_membr_prot	Family
IPR008075	LIMR	Family

Pfam: PF04791

UniProt features (28 total): topological domain 10, transmembrane region 9, sequence conflict 4, splice variant 2, chain 1, coiled-coil region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WVP7-F1	79.49	0.30

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 264 (showing top): GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, MARTINEZ_RB1_TARGETS_DN, GOBP_APPENDAGE_DEVELOPMENT, ATTCTTT_MIR186, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_EMBRYO_DEVELOPMENT, ACEVEDO_LIVER_CANCER_UP, MARTINEZ_RB1_AND_TP53_TARGETS_UP, NUYTTEN_NIPP1_TARGETS_DN, GOBP_EMBRYONIC_MORPHOGENESIS, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GSE13762_CTRL_VS_125_VITAMIND_DAY12_DC_DN

GO Biological Process (2): signal transduction (GO:0007165), embryonic digit morphogenesis (GO:0042733)

GO Molecular Function (2): transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
embryonic limb morphogenesis	1
embryonic morphogenesis	1
signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LMBR1	ZP2	Q05996	958
LMBR1	SHH	Q15465	873
LMBR1	MNX1	P50219	857
LMBR1	RNF32	Q9H0A6	796
LMBR1	NOM1	Q5C9Z4	728
LMBR1	HAND2	P61296	610
LMBR1	GLI1	P08151	544
LMBR1	RBM33	Q96EV2	542
LMBR1	GLI3	P10071	527
LMBR1	BHLHA9	Q7RTU4	519
LMBR1	ZIC2	O95409	503
LMBR1	EN2	P19622	502
LMBR1	HOXD13	P35453	479
LMBR1	GAS1	P54826	473
LMBR1	MIMS2	Q96KR6	452

IntAct

72 interactions, top by confidence:

A	B	Type	Score
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
LEPROTL1	LMBR1	psi-mi:“MI:0915”(physical association)	0.560
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
LRFN4	RIMOC1	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
SLC22A9	GPR89A	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
TMEM95	EXTL3	psi-mi:“MI:0914”(association)	0.530
GPR161	USP12	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
	WFS1	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
CMTM5	TMEM120B	psi-mi:“MI:0914”(association)	0.350
CLEC2D	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
CACNG1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
LRP3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PDE3A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
C11orf87	KLRG2	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350
KLRC4	RAP1BL	psi-mi:“MI:0914”(association)	0.350
DGCR2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
TMEM59	GPR89A	psi-mi:“MI:0914”(association)	0.350

BioGRID (131): LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS)

ESM2 similar proteins: A0PK00, A1L2R7, A2BIE7, A2VE61, A3KNK1, A6QPF8, A7XZ53, A8DZH4, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O35052, P58749, P98191, Q05B45, Q0VFK3, Q15035, Q17QL9, Q1LY80, Q3TA38, Q3UMR5, Q5EAX9, Q5EAY8, Q5FWV6, Q5HZE2, Q5R7B1, Q5U239, Q5ZMP3, Q63ZG0, Q68EY2, Q6DE21, Q6ZMG9, Q8BXA5, Q8C172, Q8C1E7, Q8CIF6, Q8N5B7, Q8NBJ9, Q8WVP7

Diamond homologs: Q4R7X9, Q5RBY7, Q5U4X7, Q6UX01, Q7ZUA6, Q7ZX75, Q803C7, Q8WVP7, Q9D1E5, Q9JIT0, Q9VC35

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

579 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	7
Uncertain significance	276
Likely benign	100
Benign	133

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1070638	NC_000007.14:g.156728717CT[1]	Pathogenic
155921	NC_000007.14:g.156791472C>G	Pathogenic
155922	LMBR1, 73-KB DUP	Pathogenic
157546	NC_000007.14:g.156785414_156802057dup	Pathogenic
157547	NC_000007.14:g.156771162_156817938dup	Pathogenic
157548	NC_000007.14:g.156778086_156854056dup	Pathogenic
30496	NC_000007.14:g.156791579C>T	Pathogenic
30497	NC_000007.14:g.156791542A>C	Pathogenic
3061990	NC_000007.14:g.156791548G>C	Pathogenic
3340528	NC_000007.14:g.156791257G>A	Pathogenic
4896	NC_000007.14:g.(156823109_156823909)_(156828009_156829209)del	Pathogenic
4897	NM_022458.4(LMBR1):c.423+4618C>G	Pathogenic
4898	NM_022458.4(LMBR1):c.423+4917G>A	Pathogenic
4899	NM_022458.4(LMBR1):c.423+4818A>T	Pathogenic
4900	NM_022458.4(LMBR1):c.423+4842T>C	Pathogenic
4902	NM_022458.4(LMBR1):c.423+5252A>G	Pathogenic
4903	NM_022458.4(LMBR1):c.423+5134C>G	Pathogenic
4905	LMBR1, 235-KB DUP, IVS5	Pathogenic
4906	NM_022458.4(LMBR1):c.423+4808T>C	Pathogenic
585197	GRCh37/hg19 7q36.3(chr7:156460343-156682575)x3	Pathogenic
1184853	Single allele	Likely pathogenic
155923	NM_022458.4(LMBR1):c.423+4919A>G	Likely pathogenic
1929405	NM_022458.4(LMBR1):c.423+5256T>G	Likely pathogenic
3245929	NC_000007.13:g.(?156583771)(156589206_?)dup	Likely pathogenic
3344248	NC_000007.14:g.156791471A>G	Likely pathogenic
3899562	NM_022458.4(LMBR1):c.423+4914A>G	Likely pathogenic
4845717	NM_022458.4(LMBR1):c.424-1G>C	Likely pathogenic

SpliceAI

5056 predictions. Top by Δscore:

Variant	Effect	Δscore
7:156675861:CAGG:C	donor_loss	1.0000
7:156675864:GT:G	donor_loss	1.0000
7:156675865:T:A	donor_loss	1.0000
7:156688032:AGGG:A	donor_gain	1.0000
7:156724105:AACTT:A	donor_loss	1.0000
7:156724106:ACTT:A	donor_loss	1.0000
7:156724107:CTT:C	donor_loss	1.0000
7:156724108:TTA:T	donor_loss	1.0000
7:156724109:T:TG	donor_loss	1.0000
7:156724110:A:AC	donor_gain	1.0000
7:156724110:A:AG	donor_loss	1.0000
7:156724110:AC:A	donor_gain	1.0000
7:156724111:C:CC	donor_gain	1.0000
7:156724111:CC:C	donor_gain	1.0000
7:156724175:TGATC:T	acceptor_loss	1.0000
7:156724178:TC:T	acceptor_loss	1.0000
7:156724179:C:CC	acceptor_gain	1.0000
7:156724179:C:T	acceptor_loss	1.0000
7:156724180:T:A	acceptor_loss	1.0000
7:156724182:T:C	acceptor_gain	1.0000
7:156724182:T:TC	acceptor_gain	1.0000
7:156724184:A:AC	acceptor_gain	1.0000
7:156724184:A:C	acceptor_gain	1.0000
7:156728008:C:CC	acceptor_gain	1.0000
7:156728642:A:AC	donor_gain	1.0000
7:156728643:C:CC	donor_gain	1.0000
7:156728643:CTGT:C	donor_gain	1.0000
7:156734253:CAGCC:C	acceptor_gain	1.0000
7:156756387:ACAT:A	donor_loss	1.0000
7:156756388:CATA:C	donor_loss	1.0000

AlphaMissense

3163 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:156724143:G:C	S398R	0.999
7:156724143:G:T	S398R	0.999
7:156724145:T:G	S398R	0.999
7:156725499:C:T	G365D	0.999
7:156725500:C:G	G365R	0.999
7:156762167:G:C	F217L	0.999
7:156762167:G:T	F217L	0.999
7:156762169:A:G	F217L	0.999
7:156762183:C:T	G212D	0.999
7:156762184:C:G	G212R	0.999
7:156763126:C:G	G201R	0.999
7:156763126:C:T	G201R	0.999
7:156763732:C:G	G163R	0.999
7:156763732:C:T	G163R	0.999
7:156796409:C:G	G135R	0.999
7:156796438:G:C	P125R	0.999
7:156796487:A:G	W109R	0.999
7:156796487:A:T	W109R	0.999
7:156826629:A:G	W99R	0.999
7:156826629:A:T	W99R	0.999
7:156688056:A:T	V454D	0.998
7:156688147:A:G	W424R	0.998
7:156688147:A:T	W424R	0.998
7:156724135:A:G	L401P	0.998
7:156762168:A:G	F217S	0.998
7:156762184:C:A	G212C	0.998
7:156763125:C:T	G201E	0.998
7:156796415:A:G	S133P	0.998
7:156796438:G:T	P125H	0.998
7:156826625:A:G	L100P	0.998

dbSNP variants (sampled 300 via entrez): RS1000029827 (7:156779111 C>T), RS1000060292 (7:156868254 T>G), RS1000100545 (7:156858864 G>A), RS1000103023 (7:156779395 T>C), RS1000105025 (7:156818548 T>A,C), RS1000105097 (7:156892118 G>A,C), RS1000106630 (7:156812741 A>G), RS1000107224 (7:156854532 C>G), RS1000108724 (7:156698991 G>A), RS1000115277 (7:156688457 G>A), RS1000117914 (7:156815177 T>A,G), RS1000133963 (7:156701486 A>C), RS1000138807 (7:156828229 T>C), RS1000139967 (7:156772407 T>C), RS1000174859 (7:156788202 A>C)

Disease associations

OMIM: gene MIM:605522 | disease phenotypes: MIM:142945, MIM:200500, MIM:174500, MIM:188740, MIM:190605, MIM:186200, MIM:135750

GenCC curated gene-disease

Disease	Classification	Inheritance
polydactyly of a triphalangeal thumb	Strong	Autosomal dominant
acheiropody	Strong	Autosomal recessive
laurin-Sandrow syndrome	Strong	Autosomal dominant
triphalangeal thumb-polysyndactyly syndrome	Strong	Autosomal dominant
syndactyly type 4	Strong	Autosomal dominant
hypoplastic tibiae-postaxial polydactyly syndrome	Supportive	Autosomal dominant

Mondo (12): holoprosencephaly 3 (MONDO:0007733), acheiropody (MONDO:0008700), polydactyly of a triphalangeal thumb (MONDO:0008270), tibia, hypoplasia or aplasia of, with polydactyly (MONDO:0008572), triphalangeal thumb-polysyndactyly syndrome (MONDO:0017454), syndactyly type 4 (MONDO:0008515), laurin-Sandrow syndrome (MONDO:0007615), skeletal dysplasia (MONDO:0018230), congenital limb malformation (MONDO:0019054), strabismus (MONDO:0003432), congenital pulmonary veins anomaly (MONDO:0020295), (MONDO:0018052)

Orphanet (12): Holoprosencephaly (Orphanet:2162), Isolated acheiropodia (Orphanet:931), Patterson-Stevenson-Fontaine syndrome (Orphanet:2439), Triphalangeal thumb-polysyndactyly syndrome (Orphanet:2950), Hypoplastic tibiae-postaxial polydactyly syndrome (Orphanet:3332), Polydactyly of a triphalangeal thumb (Orphanet:93336), Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (Orphanet:988), Syndactyly type 4 (Orphanet:93405), Laurin-Sandrow syndrome (Orphanet:2378), Primary bone dysplasia (Orphanet:364526), Congenital limb malformation (Orphanet:68378), Congenital pulmonary veins anomaly (Orphanet:98729)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000238	Hydrocephalus
HP:0000271	Abnormality of the face
HP:0000316	Hypertelorism
HP:0000366	Abnormality of the nose
HP:0000430	Underdeveloped nasal alae
HP:0000448	Prominent nose
HP:0000457	Depressed nasal ridge
HP:0000944	Abnormal metaphysis morphology
HP:0001159	Syndactyly
HP:0001161	Hand polydactyly
HP:0001162	Postaxial hand polydactyly
HP:0001172	Abnormal thumb morphology
HP:0001177	Preaxial hand polydactyly
HP:0001199	Triphalangeal thumb
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001376	Limitation of joint mobility
HP:0001501	6 metacarpals
HP:0001769	Broad foot
HP:0001770	Toe syndactyly
HP:0001773	Short foot
HP:0001829	Foot polydactyly
HP:0001841	Preaxial foot polydactyly
HP:0001883	Talipes
HP:0002000	Short columella
HP:0002714	Downturned corners of mouth
HP:0002990	Fibular aplasia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003050_23	Schizophrenia	4.000000e-06
GCST008156_34	Hip circumference adjusted for BMI	6.000000e-07
GCST009391_1435	Metabolite levels	1.000000e-07
GCST009391_1814	Metabolite levels	6.000000e-07
GCST009391_1825	Metabolite levels	4.000000e-06
GCST009391_933	Metabolite levels	6.000000e-06
GCST90002388_410	Lymphocyte count	2.000000e-09
GCST90002389_166	Lymphocyte percentage of white cells	1.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0010409	triacylglycerol 50:2 measurement
EFO:0010404	triacylglycerol 48:1 measurement
EFO:0010405	triacylglycerol 48:2 measurement
EFO:0010401	triacylglycerol 46:1 measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D013285	Strabismus	C10.292.562.887; C11.590.810
C535564	Absence of tibia with polydactyly (supp.)
C536014	Acheiropodia (supp.)
C564181	Holoprosencephaly 3 (supp.)
C535689	Laurin-Sandrow syndrome (supp.)
C566092	Syndactyly, Type IV (supp.)
C566046	Tibia, Hypoplasia of, with Polydactyly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	3
Particulate Matter	affects cotreatment, decreases expression, increases abundance, increases expression	3
Benzo(a)pyrene	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	affects methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
nickel sulfate	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
bisphenol S	increases methylation	1
NSC 689534	affects binding, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Malathion	increases expression	1
Methyl Methanesulfonate	decreases expression	1

Clinical trials (associated diseases)

109 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00461656	PHASE4	COMPLETED	Povidone-iodine Antisepsis for Strabismus Surgery
NCT01901588	PHASE4	COMPLETED	Efficacy of Single-Shot Dexmedetomidine Versus Placebo in Preventing Pediatric Emergence Delirium in Strabismus Surgery
NCT02379546	PHASE4	COMPLETED	The Effect of Anaesthesia Depth on Oculo-cardiac Reflex
NCT03349515	PHASE4	COMPLETED	The Effect of Povidone-iodine Ophthalmic Surgical Prep Solution on Respiration in Children Undergoing Strabismus Surgery With General Anesthesia.
NCT04549844	PHASE4	UNKNOWN	Peribulbar Block for Prevention of Oculocardiac Reflex
NCT06035757	PHASE4	RECRUITING	The Occurrence of Emergence Agitation in Pediatric Strabismus Surgery
NCT06560268	PHASE4	NOT_YET_RECRUITING	Low Flow Anesthesia in Children Undergoing Strabismus Surgery
NCT00000128	PHASE3	UNKNOWN	A Trial of Bifocals in Myopic Children With Esophoria
NCT00001864	PHASE3	COMPLETED	Amblyopia (Lazy Eye) Treatment Study
NCT00038753	PHASE3	UNKNOWN	Vision In Preschoolers Study (VIP Study)
NCT01584843	PHASE3	COMPLETED	Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Strabismus
NCT04060771	PHASE3	UNKNOWN	Post-Operative Nausea and Vomiting in Children Submitted to Strabismus Surgery
NCT06863675	PHASE3	NOT_YET_RECRUITING	Highly Aspherical Lenslet (HAL) and Binocular Vision (BV) Disorders [HALT X(T) Study]
NCT00478907	PHASE2	COMPLETED	Prevention of Complications of Eye Surgery
NCT06689943	PHASE2	NOT_YET_RECRUITING	Pain After Strabismus Surgery
NCT00917982	PHASE1	UNKNOWN	The Effect of Vision Therapy/Orthoptic on Motor & Sensory Status of the 3 to 7 Years Old Strabismic Patients
NCT02246556	PHASE1	TERMINATED	Dichoptic Virtual Reality Therapy for Amblyopia in Adults
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients
NCT01616108	PHASE2/PHASE3	UNKNOWN	Bupivacaine Injection of Eye Muscles to Treat Strabismus
NCT00001143	Not specified	COMPLETED	Development of the Eye Motor System During the First 7 Months of Life in Infants With and Without a Family History of Cross-Eye
NCT00001861	Not specified	COMPLETED	Screening for Studies on Nystagmus and Strabismus
NCT00304577	Not specified	COMPLETED	Bilateral Recession or Unilateral Recession-Resection as Surgery for Infantile Esotropia
NCT00338559	Not specified	COMPLETED	Does LMA Instead of ET Tube Affect Incidence of Postoperative Vomiting in Children Undergoing Strabismus Correction?
NCT00535938	Not specified	COMPLETED	MDs on Botox Utility (MOBILITY)
NCT00559234	Not specified	COMPLETED	Potential Research Participants for Future Studies of Inherited Eye Diseases
NCT01109459	Not specified	COMPLETED	Multimodal Physician Intervention to Detect Amblyopia
NCT01430247	Not specified	COMPLETED	Vision Screening for the Detection of Amblyopia
NCT01512355	Not specified	COMPLETED	The Effect of Dexmedetomidine on Decreasing Emergence Agitation and Delirium in Pediatric Patients Undergoing Strabismus Surgery
NCT01608828	Not specified	COMPLETED	Assessing the Functional and Psychosocial Impact of Strabismus in Asian Children Using the AS-20 and IXTQ Questionnaires
NCT01706991	Not specified	COMPLETED	Amblyopia and Strabismus Detection Using a Pediatric Vision Scanner
NCT01726842	Not specified	COMPLETED	Amblyopia and Strabismus Detection Using a Pediatric Vision Scanner
NCT01791946	Not specified	COMPLETED	Binocular Treatment of Amblyopia Before and After Strabismus Surgery
NCT01812044	Not specified	COMPLETED	Postoperative Subtenons Anesthesia for Postoperative Pain in Pediatric Strabismus Surgery
NCT01832883	Not specified	COMPLETED	Amblyopia and Strabismus Detection Using a Pediatric Vision Scanner