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.957-11C>G

CA626689269

978048 (ClinVar)

Gene: SGCA (HGNC:6442)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: 03500fe4-c6cb-4d45-8fb2-d65d5a1d8a10

Approved on: 2025-01-08

Published on: 2025-01-08

HGVS expressions

NM_000023.4:c.957-11C>G

NM_000023.4(SGCA):c.957-11C>G

NC_000017.11:g.50170629C>G

CM000679.2:g.50170629C>G

NC_000017.10:g.48247990C>G

CM000679.1:g.48247990C>G

NC_000017.9:g.45602989C>G

NG_008889.1:g.9625C>G

ENST00000504073.2:c.807-11C>G

ENST00000511303.6:n.310-11C>G

ENST00000512526.2:c.576-11C>G

ENST00000682109.1:c.837-11C>G

ENST00000683226.1:n.1555-11C>G

ENST00000683294.1:c.*60-11C>G

ENST00000683544.1:n.600C>G

ENST00000262018.8:c.957-11C>G

ENST00000262018.7:c.957-11C>G

ENST00000344627.10:c.585-11C>G

ENST00000504073.1:c.274-11C>G

ENST00000511303.5:c.306-11C>G

ENST00000512526.1:c.420-11C>G

ENST00000513821.5:c.748-11C>G

ENST00000513942.5:n.376-11C>G

NM_000023.2:c.957-11C>G

NM_001135697.1:c.585-11C>G

NM_000023.3:c.957-11C>G

NM_001135697.2:c.585-11C>G

NR_135553.1:n.804-11C>G

NM_001135697.3:c.585-11C>G

NR_135553.2:n.784-11C>G

Likely Pathogenic

PM2_Supporting PP4_Strong PP3 PM3

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

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.957-11C>G variant in SGCA is an intronic variant located in intron 7 of 9. This variant has been detected in at least two individuals with autosomal recessive limb girdle muscular dystrophy, where it was identified in unknown phase or confirmed in trans with a pathogenic or likely pathogenic variant (c.229C>T p.(Arg77Cys), 0.5 pts, PMID: 32153140; c.850C>T p.(Arg284Cys), 1.0 pt, UCSD internal clinic data communication) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as significantly reduced or absent expression of encoded alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong, UCSD internal clinic data communication). The highest minor allele frequency of this variant is 0.00002940 (2/68034 genome chromosomes) in the European (non-Finnish) population of gnomAD v3.1.2, which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (0.00009), meeting this criterion (PM2_Supporting). SpliceAI predicts the loss of the native acceptor site with a score of 0.49 and gain of a cryptic site with a score of 0.63, meeting criteria for 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; 01/08/2025): PP4_Strong, PM3, PP3, PM2_Supporting.

PM2_Supporting

The highest minor allele frequency of this variant is 0.00002940 (2/68034 genome chromosomes) in the European (non-Finnish) population of gnomAD v3.1.2, which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (0.00009), meeting this criterion (PM2_Supporting).

PP4_Strong

At least one patient with this variant displayed progressive limb girdle muscle weakness as well as significantly reduced or absent expression of alpha-sarcoglycan protein, which is highly specific for SGCA-related LGMD (PP4_Strong; internal clinic data).

PP3

SpliceAI predicts the loss of the native acceptor site with a score of 0.49 and gain of a cryptic site with a score of 0.63, meeting criteria for PP3.

PM3

This variant has been detected in at least two individuals with autosomal recessive limb girdle muscular dystrophy, where it was identified in unknown phase or confirmed in trans with a pathogenic or likely pathogenic variant (1.5 pts, PMID: 32153140, internal clinic data) (PM3).

BA1