SGCA p.Arg34Cys

The NM_000023.4: c.100C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 34 (p.Arg34Cys). This variant has been reported in at least three patients with symptoms of limb girdle muscular dystrophy (PMID: 7663524, 21031578; Washington University internal clinic data communication), including in a homozygous state in one patient from a consanguineous family (0.25 pts) and confirmed in trans with a SGCA variant not yet curated by the VCEP and considered VUS (0.25 pts) (PM3_Supporting). At least one patient with this variant displayed progressive muscle weakness and significantly reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 7663524, 21031578, Washington University internal clinic data communication). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 7663524). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113724 alleles) in the European (non-Finnish) population, which is lower than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another missense variant at the same codon, c.101G>A (p.Arg34His), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PM5_Supporting). 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; 01/09/2025): PM3_Supporting, PP4_Strong, PM5_Supporting, PP3, PM2_Supporting, PP1.