SGCA

protein-coding

sarcoglycan alpha

Gene summary

This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

Previous symbols:

MANE transcript

NM_000023.4

Inheritance

ClinVar variants

P:219U:210B:223

Top phenotype

Muscular dystrophy, limb-girdle, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr17:50,164,214-50,175,928

External References & Databases

Ensembl (ENSG00000108823)

Transcript & Mutation Effects

hg38 • Region Span ~11.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive limb-girdle muscular dystrophy type 2DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011968

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

autosomal recessive limb-girdle muscular dystrophy type 2DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011968

Submitter: Natera

autosomal recessive limb-girdle muscular dystrophy type 2DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011968

Submitter: Myriad Women's Health

autosomal recessive limb-girdle muscular dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: PanelApp Australia

autosomal recessive limb-girdle muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

Evidence indicating a relationship between variants in SGCA and autosomal recessive muscular dystrophy was reported by Roberds et al., 1994 (PMID: 8069911), in which variants in SGCA were found to segregate in a large French family that showed linkage analysis implicating chromosome 17 with limb girdle muscular dystrophy (Romero et al., 1994; PMID: 7987694). Limb girdle muscular dystrophy (LGMD) is characterized by progressive muscle weakness of proximal limb with age, which can lead to difficulty walking or complete loss of ambulation requiring wheel chair use. Other phenotypic features associated include scapular winging, calf pseudo hypertrophy, contractors, and in some cases cardiomyopathy (PMID: 22303798, 19781108 ). Numerous variants have been reported, in both ClinVar and in LOVD (https://databases.lovd.nl/shared/genes/SGCA). Further, the p.Arg77Cys variant is a known founder variant and has been estimated to account for ~30% of autosomal recessive LGMD associated with SGCA (PMID: 9192266, 15736300, 8528203). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available, however the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. The mechanism for the gene-disease relationship is protein loss of function, as SGCA encodes alpha-sarcoglycan, an essential component of the dystrophin-glycoprotein complex (PMID: 19781108) present in striated muscle costameres which function in muscle contraction. In summary, SGCA is definitively associated with autosomal recessive limb girdle muscular dystrophy (MONDO:0015152). 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 02/07/20 (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 dystrophy type 2DSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011968

Submitter: Orphanet

autosomal recessive limb-girdle muscular dystrophy type 2DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011968

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Muscular dystrophy, limb-girdle, autosomal recessive 3AR

Manifestation: Cardiovascular; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can include severe cardiac manifestations, 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

Refs: 8069911; 7987694; 8528203; 7663524; 9032047; 18285821; 20627570

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SGCA variants in ClinVar

17 Conditions Cataloged

Autosomal recessive limb-girdle muscular dystrophy type 2DTotal: 747

not providedTotal: 183

not specifiedTotal: 72

Inborn genetic diseasesTotal: 44

Autosomal recessive limb-girdle muscular dystrophyTotal: 42

SGCA-related disorderTotal: 37

SarcoglycanopathyTotal: 28

Abnormality of the musculatureTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000023.4. 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		1 clinvar	13 clinvar	208 clinvar	1 clinvar	223
missense	16 clinvar	67 clinvar	193 clinvar	13 clinvar	1 clinvar	290
nonsense	9 clinvar	15 clinvar				24
start loss		2 clinvar				2
frameshift	31 clinvar	46 clinvar	1 clinvar			78
splice donor/acceptor (+/-2bp)	6 clinvar	26 clinvar	3 clinvar			35
Total	62	157	210	221	2	652

Highest pathogenic variant AF is 0.00046966044

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000023.4	RefSeq	NP_000014.1	9	MANE Select
ENST00000262018.8	Ensembl	ENSP00000262018.3	9	MANE Select
NM_001135697.3	RefSeq	NP_001129169.1	7	Standard
ENST00000344627.10	Ensembl	ENSP00000345522.6	7	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 contraction
muscle organ development

Molecular Function

calcium ion binding
protein binding

Cellular Component

cytoplasm
cytoskeleton
cell-cell junction
dystrophin-associated glycoprotein complex
sarcoglycan complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262018
Coding exons: 9
Length: 11718
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125748
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.676	214	244	0.878	0.0000162	2445
Missense (PolyPhen)		68	85.262	0.79754		880
Synonymous	0.108	99	100	0.986	0.00000648	836
Loss of Function	2.19	7	16.7	0.420	8.08e-7	181

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

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.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.0528
RVIS EVS: -0.71
RVIS percentile EVS: 14.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.554

Gene Damage Prediction

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