ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.100C>T (p.Arg34Cys)

gnomAD frequency: 0.00002  dbSNP: rs758647756
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen RCV004998420 SCV005620263 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-09 reviewed by expert panel curation 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.
Athena Diagnostics RCV000201165 SCV000255836 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2012-12-31 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000493338 SCV000332844 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
GeneDx RCV000493338 SCV000581759 likely pathogenic not provided 2024-04-16 criteria provided, single submitter clinical testing Observed in apparent homozygous state or in the presence of a second SGCA pathogenic variant, phase unknown, in patients with SGCA-related limb-girdle muscular dystrophy in the literature and not observed in homozygous state in controls (PMID: 9192266, 9153448, 27906075, Lekshmi_2022_CaseReport); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9153448, 19781108, 9192266, 26944168, Lekshmi2022[casereport], 30564623, 21031578, 27906075, 32528171)
Revvity Omics, Revvity RCV000201165 SCV002020087 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-05-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000201165 SCV002228803 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2024-08-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the SGCA protein (p.Arg34Cys). This variant is present in population databases (rs758647756, gnomAD 0.0009%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 9192266, 21031578, 27906075, 32528171). ClinVar contains an entry for this variant (Variation ID: 217250). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg34 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7663524, 9032047, 26944168). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000201165 SCV003931629 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2023-02-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV000201165 SCV004203158 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2024-03-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000201165 SCV005649531 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2024-06-21 criteria provided, single submitter clinical testing

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