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.662G>C (p.Arg221Pro)

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CA400180670

497670 (ClinVar)

Gene: SGCA

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e203815d-e310-4737-9fca-d20939ca73c3

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_000023.4:c.662G>C

NM_000023.4(SGCA):c.662G>C (p.Arg221Pro)

NC_000017.11:g.50169169G>C

CM000679.2:g.50169169G>C

NC_000017.10:g.48246530G>C

CM000679.1:g.48246530G>C

NC_000017.9:g.45601529G>C

NG_008889.1:g.8165G>C

ENST00000504073.2:c.597+65G>C

ENST00000511303.6:n.309+597G>C

ENST00000512526.2:c.575+597G>C

ENST00000682109.1:c.542G>C

ENST00000683226.1:n.372G>C

ENST00000683294.1:c.662G>C

ENST00000262018.8:c.662G>C

ENST00000262018.7:c.662G>C

ENST00000344627.10:c.584+597G>C

ENST00000502555.5:c.*321G>C

ENST00000504073.1:c.64+65G>C

ENST00000511303.5:c.305+597G>C

ENST00000512526.1:c.419+597G>C

ENST00000513821.5:c.662G>C

ENST00000513942.5:n.375+597G>C

NM_000023.2:c.662G>C

NM_001135697.1:c.584+597G>C

NM_000023.3:c.662G>C

NM_001135697.2:c.584+597G>C

NR_135553.1:n.718G>C

NM_001135697.3:c.584+597G>C

NR_135553.2:n.698G>C

Likely Pathogenic

PP3 PM3 PP4_Strong PM2_Supporting

PS4 PS2 PS3 PS1 PP1 PP2 PM1 PM4 PM5 PM6 PVS1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP5 BP7 BA1

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000023.4: c.662G>C variant in SGCA is a missense variant predicted to cause substitution of arginine by proline at amino acid 221 (p.Arg221Pro). This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Washington University internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, Washington University internal clinic data communication). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). 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 1.0.0; 01/07/2025): PM2_Supporting, PP3, PM3, PP4_Strong.

PP3

The computational predictor REVEL gives a score of 0.765, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3).

PM3

This variant has been detected in at least one individual with autosomal recessive limb girdle muscular dystrophy who was compound heterozygous for the variant and a pathogenic variant (c.585-1G>A, 1.0 pt, Internal laboratory contributor) (PM3).

PP4_Strong

At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, internal laboratory contributor).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).

PS4