SGCB

protein-coding

sarcoglycan beta

Gene summary

This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

Previous symbols:

LGMD2E

MANE transcript

NM_000232.5

Inheritance

ClinVar variants

P:143U:166B:154

Top phenotype

Muscular dystrophy, limb-girdle, autosomal recessive, 4

gnomAD constraint

pLI —, LoF o/e 0.87

Max pathogenic AF

—

Genomic locus

chr4:52,020,706-52,038,299

External References & Databases

Ensembl (ENSG00000163069)

Transcript & Mutation Effects

hg38 • Region Span ~17.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive limb-girdle muscular dystrophy type 2ESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011423

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive limb-girdle muscular dystrophy type 2ESUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011423

Submitter: Orphanet

autosomal recessive limb-girdle muscular dystrophy type 2EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011423

Submitter: Natera

autosomal recessive limb-girdle muscular dystrophy type 2EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011423

Submitter: Myriad Women's Health

autosomal recessive limb-girdle muscular dystrophy type 2EDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011423

Submitter: Ambry Genetics

autosomal recessive limb-girdle muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

The relationship between SGCB and limb girdle muscular dystrophy (LGMD; also known as LGMD 2E and LGMD R4) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. The SGCB gene is located on chromosome 4q12, 4.4 kb long with 6 exons encoding a 318-amino acid protein. At least 15 pathogenic variants reported in humans with autosomal recessive LGMD are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Limb girdle muscular dystrophy is characterized by progressive muscle weakness, mostly in the proximal muscles and affecting the pelvic and shoulder girdle, accompanied by an elevated serum creatine kinase and the loss of the ability to walk before the age of 20. Cardiomyopathy is also an accompanying feature in some individuals. SGCB has been reported in association with autosomal recessive LGMD as early as 1995 by Lim et al and Bonnemann et al (PMIDs: 7581449, 7581448). Summary of Case Level Data (12 points): The association is seen in at least 13 probands in 7 publications (PMID: 30919934, 25862795, 8968749, 28687063, 10662809, 7581449, 7581448). Variants in this gene segregated with disease in 6 additional family members. At least two founder variants have been reported in this gene in the Southern Indiana Amish (Thr151Arg) and the Dutch (Ser114Phe) populations. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease has been reported to be biallelic loss of function. Summary of Experimental Data (5.5 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. SGCB encodes β-sarcoglycan, a subunit of the sarcoglycan complex, which is a component of the dystrophin-glycoprotein complex stabilizing the sarcolemma (PMID: 7581448). β-sarcoglycan is ubiquitously expressed but is most strongly expressed in the striated muscle, heart and smooth muscle (PMID: 7581448). β-sarcoglycan interacts with δ-Sarcoglycan, encoded by SGCD, to form the core and initiate assembly of the sarcoglycan complex (PMID: 9864373). Sgcb-null mice recapitulate the human phenotype, displaying elevated creatine kinase levels and histopathological features of muscular dystrophy and cardiomyopathy (PMID: 10678176, 10441321). AAV-mediated delivery of the human SGCB transgene resulted in lowering of creatine kinase levels, partial correction of cardiac functional deficits and recovery of the diaphragm muscle (PMID: 28284983). In summary, the SGCB-autosomal recessive limb-girdle muscular dystrophy gene-disease relationship is definitive. 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 Limb-Girdle Muscular Dystrophy GCEP on February 11, 2020 (SOP Version 7). This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.

autosomal recessive limb-girdle muscular dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Muscular dystrophy, limb-girdle, autosomal recessive, 4AR

Manifestation: Cardiovascular; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can include severe cardiac manifestations, including lethal ventricular arrhythmias and dilated cardiomyopathy and knowledge may allow surveillance (eg, with EKG, echocardiogram, and Holter monitoring) and early medical management, which may ameliorate morbidity and mortality; Heart transplantation may be indicated in individuals with severe dilated cardiomyopathy

Comments: Digenic inheritance (with SGCD) has been suggested, but the evidence is unclear

Refs: 7581448; 8968749; 7581449; 18285821; 20627570

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SGCB variants in ClinVar

13 Conditions Cataloged

Autosomal recessive limb-girdle muscular dystrophy type 2ETotal: 541

not providedTotal: 116

not specifiedTotal: 32

Autosomal recessive limb-girdle muscular dystrophyTotal: 23

SGCB-related disorderTotal: 20

Qualitative or quantitative defects of beta-sarcoglycanTotal: 19

Inborn genetic diseasesTotal: 13

Primary dilated cardiomyopathyTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000232.5. 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			7 clinvar	147 clinvar		154
missense	6 clinvar	15 clinvar	155 clinvar	5 clinvar	2 clinvar	183
nonsense	9 clinvar	8 clinvar				17
start loss	4 clinvar	4 clinvar				8
frameshift	39 clinvar	38 clinvar	2 clinvar			79
splice donor/acceptor (+/-2bp)	5 clinvar	15 clinvar	2 clinvar			22
Total	63	80	166	152	2	463

Highest pathogenic variant AF is 0.0004685757

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000232.5	RefSeq	NP_000223.1	6	MANE Select
ENST00000381431.10	Ensembl	ENSP00000370839.6	6	MANE Select
NM_001440519.1	RefSeq	NP_001427448.1	5	Standard
NM_001440520.1	RefSeq	NP_001427449.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Dilated cardiomyopathy (DCM) - Homo sapiens (human)
Viral myocarditis - Homo sapiens (human)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
Arrhythmogenic Right Ventricular Cardiomyopathy

Biological Process

muscle organ development
muscle fiber development
cardiac muscle cell development
vascular smooth muscle cell development

Cellular Component

cytoplasm
cytoskeleton
integral component of plasma membrane
dystrophin-associated glycoprotein complex
sarcoglycan complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381431
Coding exons: 6
Length: 17777
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.00497	178	178	1.00	0.00000939	2130
Missense (PolyPhen)		43	51.808	0.82999		571
Synonymous	-0.978	68	58.5	1.16	0.00000289	588
Loss of Function	0.415	10	11.5	0.868	6.34e-7	150

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.;
Disease: DISEASE: Limb-girdle muscular dystrophy 2E (LGMD2E) [MIM:604286]: An autosomal recessive degenerative myopathy characterized by pelvic and shoulder muscle wasting, onset usually in childhood and variable progression rate. {ECO:0000269|PubMed:8968749, ECO:0000269|PubMed:9032047, ECO:0000269|PubMed:9565988, ECO:0000269|PubMed:9631401}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.188
RVIS EVS: -0.23
RVIS percentile EVS: 37.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.112

Gene Damage Prediction

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