B3GALT6

protein-coding

beta-1,3-galactosyltransferase 6, the group of Beta 3-glycosyltransferases

Gene summary

The enzyme encoded by this intronless gene is a beta-1,3-galactosyltransferase found in the medial Golgi apparatus, where it catalyzes the transfer of galactose from UDP-galactose to substrates containing a terminal beta-linked galactose moiety. The encoded enzyme has a particular affinity for galactose-beta-1,4-xylose found in the linker region of glycosamines. This enzyme is required for glycosaminoglycan synthesis. [provided by RefSeq, Jun 2013]

MANE transcript

NM_080605.4

Inheritance

ClinVar variants

P:49U:216B:132

Top phenotype

Ehlers-Danlos syndrome, spondylodysplastic type, 2; Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures; Al-Gazali syndrome

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr1:1,232,237-1,235,041

External References & Databases

Ensembl (ENSG00000176022)

Transcript & Mutation Effects

hg38 • Region Span ~2.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ehlers-Danlos syndrome, spondylodysplastic type, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014139

Submitter: G2P

B3GALT6-related congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100586

Submitter: ClinGen

*B3GALT6* was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2013 (Nakajima et al., PMID: 23664117). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Al-Gazali syndrome (OMIM:609465), Ehlers-Danlos syndrome, spondylodysplastic type, 2 (OMIM:615349), and Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (OMIM:271640) and curated under the disease entity congenital disorder of glycosylation. 22 unique variants (start loss, missense, in-frame indel, and frameshift) that have been reported in 17 probands in 7 publications (PMIDs: 23664117, 25149931, 28649518, 23664118, 29230159, 34529350, 29443383) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, two reports of monogenic (autosomal dominant) inheritance have been published in the literature, but there is not enough evidence to rule out a second variant in trans (PMIDs: 23664117, 35734427). The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by an animal model (PMID: 33363150). In summary, there is definitive evidence supporting the relationship between *B3GALT6* and autosomal recessive congenital disorder of glycosylation. 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 Congenital Disorders of Glycosylaton GCEP on the meeting date January 15, 2025 (SOP Version 11).

spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fracturesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010075

Submitter: G2P

spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fracturesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010075

Submitter: Labcorp Genetics (formerly Invitae)

Ehlers-Danlos syndrome, spondylodysplastic type, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014139

Submitter: Labcorp Genetics (formerly Invitae)

B3GALT6-related congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100586

Submitter: PanelApp Australia

spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fracturesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010075

Submitter: Genomics England PanelApp

Ehlers-Danlos syndrome, spondylodysplastic type, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014139

Submitter: Genomics England PanelApp

Ehlers-Danlos syndrome, spondylodysplastic type, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014139

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ehlers-Danlos syndrome, spondylodysplastic type, 2; Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures; Al-Gazali syndromeAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23664117; 23664118; 25149931; 29443383

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to B3GALT6 variants in ClinVar

14 Conditions Cataloged

Ehlers-Danlos syndrome, spondylodysplastic type, 2Total: 289

Spondyloepimetaphyseal dysplasia with joint laxityTotal: 275

not providedTotal: 127

not specifiedTotal: 86

Inborn genetic diseasesTotal: 77

Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fracturesTotal: 27

B3GALT6-related disorderTotal: 26

Al-Gazali syndromeTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_080605.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	122 clinvar		130
missense	9 clinvar	10 clinvar	195 clinvar	8 clinvar	2 clinvar	224
nonsense	4 clinvar	5 clinvar	3 clinvar			12
start loss	4 clinvar	4 clinvar				8
frameshift	5 clinvar	8 clinvar	10 clinvar			23
splice donor/acceptor (+/-2bp)						0
Total	22	27	216	130	2	397

Highest pathogenic variant AF is 0.00014479746

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_080605.4	RefSeq	NP_542172.2	1	MANE Select
ENST00000379198.5	Ensembl	ENSP00000368496.2	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate - Homo sapiens (human)
Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human)
Metabolism of carbohydrates
A tetrasaccharide linker sequence is required for GAG synthesis
Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

glycosaminoglycan biosynthetic process
protein glycosylation
heparan sulfate proteoglycan biosynthetic process
glycosaminoglycan metabolic process
chondroitin sulfate biosynthetic process

Molecular Function

galactosyltransferase activity
UDP-galactosyltransferase activity
galactosylxylosylprotein 3-beta-galactosyltransferase activity

Cellular Component

Golgi membrane
endoplasmic reticulum
Golgi apparatus
Golgi medial cisterna
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379198
Coding exons: 1
Length: 2793
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.26	93	134	0.694	0.0000112	1992
Missense (PolyPhen)		26	48.604	0.53493		698
Synonymous	0.413	61	65.2	0.935	0.00000586	751
Loss of Function	0.932	3	5.32	0.564	2.32e-7	77

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Beta-1,3-galactosyltransferase that transfers galactose from UDP-galactose to substrates with a terminal beta-linked galactose residue. Has a preference for galactose-beta-1,4-xylose that is found in the linker region of glycosaminoglycans, such as heparan sulfate and chondroitin sulfate. Has no activity towards substrates with terminal glucosamine or galactosamine residues. {ECO:0000269|PubMed:11551958}.;
Disease: DISEASE: Spondyloepimetaphyseal dysplasia with joint laxity, 1, with or without fractures (SEMDJL1) [MIM:271640]: A bone disease characterized by vertebral abnormalities and ligamentous laxity that result in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Additional skeletal features include elbow deformities with radial head dislocation, dislocated hips, clubfeet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed. {ECO:0000269|PubMed:23664117, ECO:0000269|PubMed:23664118}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.736

Gene Damage Prediction

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