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.246C>A (p.Ser82Arg)

CA400177611

813953 (ClinVar)

Gene: SGCA (HGNC:6442)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: 687cc694-7cdd-495d-80da-00e0e769be3f

Approved on: 2026-04-29

Published on: 2026-05-07

HGVS expressions

NM_000023.4(SGCA):c.246C>A (p.Ser82Arg)

NM_000023.4:c.246C>A

NC_000017.11:g.50167670C>A

CM000679.2:g.50167670C>A

NC_000017.10:g.48245031C>A

CM000679.1:g.48245031C>A

NC_000017.9:g.45600030C>A

NG_008889.1:g.6666C>A

ENST00000504073.2:c.246C>A

ENST00000511303.6:n.38-277C>A

ENST00000512526.2:c.246C>A

ENST00000682109.1:c.126C>A

ENST00000683294.1:c.246C>A

ENST00000262018.8:c.246C>A

ENST00000262018.7:c.246C>A

ENST00000344627.10:c.246C>A

ENST00000502555.5:c.157+183C>A

ENST00000511303.5:c.34-277C>A

ENST00000512526.1:c.90C>A

ENST00000513821.5:c.246C>A

ENST00000513942.5:n.104-277C>A

ENST00000514934.1:c.*18+183C>A

NM_000023.2:c.246C>A

NM_001135697.1:c.246C>A

NM_000023.3:c.246C>A

NM_001135697.2:c.246C>A

NR_135553.1:n.302C>A

NM_001135697.3:c.246C>A

NR_135553.2:n.282C>A

Likely Pathogenic

PM2_Supporting PP4 PM3 PS3_Moderate

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.246C>A variant in SGCA is a missense variant predicted to cause substitution of serine by arginine at amino acid 82, p.(Ser82Arg). This variant has been detected in at least four homozygous individuals with limb-girdle muscular dystrophy of Iranian ancestry (1 pt, ClinVar: SCV001164458.1; PMID: 39678382, 38374194, 32528171, 41315541) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMID: 32528171, 41315541). In vitro assay in a heterologous cell system has demonstrated that this variant disrupts membrane localization of the sarcoglycan complex (PS3_Moderate, Washington University internal data). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.504, which is below the threshold of 0.7 (PP3 not met). In summary, this variant meets the criteria to be classified as Likely 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, PP4, PS3_Moderate, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v4.1.1 (PM2_Supporting).

PP4

At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMID: 32528171, 41315541).

PM3

This variant has been detected in at least four homozygous individuals with limb-girdle muscular dystrophy of Iranian ancestry (1 pt, ClinVar: SCV001164458.1; PMID: 39678382, 38374194, 32528171, 41315541) (PM3). Note: Three reported cases are of Iranian origin

PS3_Moderate

In vitro assay in an heterologous cell system has demonstrated that this variant disrupts membrane localization of the sarcoglycan complex (PS3_Moderate, Washington University internal data). Variant was tested by Gabe Haller's team using their previously reported approach for SGCB variants. The assay has been clinically validated with over 11 control variants. The variant presented a score of -1, which is les than the -0.5 threshold for non-functional variants that was used for SGCB. This variant was also classified as non-functional in Monkol's membrane localization assay, which used a slightly different method.

PP3

The computational predictor REVEL gives a score of 0.504, which is below the threshold of 0.7 (PP3 not met). SpliceAI 0.03

Curation History

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