Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000023.4(SGCA):c.293G>A (p.Arg98His)

CA120423

9435 (ClinVar)

Gene: SGCA (HGNC:6442)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: a77a5d53-75ac-4487-aebe-2d62b25b9cf8

Approved on: 2026-04-29

Published on: 2026-05-07

HGVS expressions

NM_000023.4(SGCA):c.293G>A (p.Arg98His)

NM_000023.4:c.293G>A

NC_000017.11:g.50167717G>A

CM000679.2:g.50167717G>A

NC_000017.10:g.48245078G>A

CM000679.1:g.48245078G>A

NC_000017.9:g.45600077G>A

NG_008889.1:g.6713G>A

ENST00000504073.2:c.293G>A

ENST00000511303.6:n.38-230G>A

ENST00000512526.2:c.293G>A

ENST00000682109.1:c.173G>A

ENST00000683226.1:n.3G>A

ENST00000683294.1:c.293G>A

ENST00000262018.8:c.293G>A

ENST00000262018.7:c.293G>A

ENST00000344627.10:c.293G>A

ENST00000502555.5:c.158-230G>A

ENST00000511303.5:c.34-230G>A

ENST00000512526.1:c.137G>A

ENST00000513821.5:c.293G>A

ENST00000513942.5:n.104-230G>A

ENST00000514934.1:c.*19-230G>A

NM_000023.2:c.293G>A

NM_001135697.1:c.293G>A

NM_000023.3:c.293G>A

NM_001135697.2:c.293G>A

NR_135553.1:n.349G>A

NM_001135697.3:c.293G>A

NR_135553.2:n.329G>A

Pathogenic

PM2_Supporting PS3_Moderate PP4_Strong PM3_Strong

PP3

Evidence Links 0

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCA Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000023.4: c.293G>A variant in SGCA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 98, p.(Arg98His). This variant has been detected in at least six individuals with limb-girdle muscular dystrophy (PMID: 32528171, 30564623, 29382405, 12746421, 36575883; Newcastle University internal data communication). Of those individuals, three were presumed compound heterozygous (phase unconfirmed) for the variant and a pathogenic variant (c.229C>T p.(Arg77Cys), 0.5 pts, Newcastle University internal data communication; c.307A>G p.(Ile103Val), 0.5 pts, PMID: 30564623, LOVD Individual #00219726; c.850C>T p.(Arg284Cys), 0.5 pts, 29382405). Three unrelated patients were homozygous for the variant without reported consanguinity (1.0 pts, PMID: 32528171, 36575883) (PM3_Strong). At least one patient with this variant and another presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness and significantly reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 29382405). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.000037447 (33/1178322 European (non-Finnish) alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion. The variant was tested in SGCA-null mice by transduction with h-Alpha-SG-R98H in one hind-limb. The humanized limb presented signs of dystrophy in skeletal muscle and extreme reduction of alpha-sarcoglycan via immunohistochemistry and western blot (PS3_Moderate; PMID: 34505136). The computational predictor REVEL gives a score of 0.596, which is below the threshold of 0.7 (PP3 not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 04/29/2026): PM3_Strong, PP4_Strong, PS3_Moderate, PM2_Supporting.

PM2_Supporting

The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.000037447 (33/1178322 European (non-Finnish) alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion.

PS3_Moderate

The variant was tested in SGCA-null mice by transduction with h-Alpha-SG-R98H in one hind-limb. The humanized limb presented signs of dystrophy in skeletal muscle and extreme reduction of alpha-sarcoglycan via immunohistochemistry and western blot (PS3_Moderate; PMID: 34505136). -0.7 in WashU assay of membrane localization, -1.6 in Lek/Yale assay

PP4_Strong

At least one patient with this variant and another presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness and significantly reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 29382405).

PM3_Strong

This variant has been detected in at least six individuals with limb-girdle muscular dystrophy (PMID: 32528171, 30564623, 29382405, 12746421, 36575883; Newcastle University internal data communication). Of those individuals, three were presumed compound heterozygous (phase unconfirmed) for the variant and a pathogenic variant (c.229C>T p.(Arg77Cys), 0.5 pts, Newcastle University internal data communication; c.307A>G p.(Ile103Val), 0.5 pts, PMID: 30564623, LOVD Individual #00219726; c.850C>T p.(Arg284Cys), 0.5 pts, 29382405). Three unrelated patients were homozygous for the variant without reported consanguinity (1.0 pts, PMID: 32528171, 36575883) (PM3_Strong). c.307A>G p.(Ile103Val), c.229C>T p.(Arg77Cys) are all independently P co-occurrence checked

PP3

The computational predictor REVEL gives a score of 0.596, which is below the threshold of 0.7 (PP3 not met). Located 7 amino acids to the end of the exon. SpliceAI: 0.0100 Genie: NIF-ML Score: 0.0 Benign: 100% SpliceVault Top-10: Exon skipping of exon 3 seems to occur naturally and frequently according to GTEx and SRA. Conclusion: -Variant does not affect the assessed donor region (-4 to +8). -No cryptic Risk

Curation History

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