Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000023.4(SGCA):c.661C>T (p.Arg221Cys)

CA8643859

452720 (ClinVar)

Gene: SGCA
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: e5736e98-a4d7-4384-bbb0-da1f2819c0d2
Approved on: 2025-10-28
Published on: 2025-11-11

HGVS expressions

NM_000023.4:c.661C>T
NM_000023.4(SGCA):c.661C>T (p.Arg221Cys)
NC_000017.11:g.50169168C>T
CM000679.2:g.50169168C>T
NC_000017.10:g.48246529C>T
CM000679.1:g.48246529C>T
NC_000017.9:g.45601528C>T
NG_008889.1:g.8164C>T
ENST00000504073.2:c.597+64C>T
ENST00000511303.6:n.309+596C>T
ENST00000512526.2:c.575+596C>T
ENST00000682109.1:c.541C>T
ENST00000683226.1:n.371C>T
ENST00000683294.1:c.661C>T
ENST00000262018.8:c.661C>T
ENST00000262018.7:c.661C>T
ENST00000344627.10:c.584+596C>T
ENST00000502555.5:c.*320C>T
ENST00000504073.1:c.64+64C>T
ENST00000511303.5:c.305+596C>T
ENST00000512526.1:c.419+596C>T
ENST00000513821.5:c.661C>T
ENST00000513942.5:n.375+596C>T
NM_000023.2:c.661C>T
NM_001135697.1:c.584+596C>T
NM_000023.3:c.661C>T
NM_001135697.2:c.584+596C>T
NR_135553.1:n.717C>T
NM_001135697.3:c.584+596C>T
NR_135553.2:n.697C>T
More

Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM3_Strong PM5_Supporting
Not Met criteria codes 21
PS2 PS4 PS3 PS1 PP2 PM1 PM4 PM6 PM2 PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 BA1

Evidence Links 0

Expert Panel

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.661C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 221, p.(Arg221Cys). This variant has been identified in at least eight individuals with a clinical suspicion of limb girdle muscular dystrophy (PMID: 35416532, 28403181, 30564623, 32528171, 32875335; LOVD SGCA_000169; John Walton Muscular Dystrophy Research Centre internal data communication; ClinVar SCV000941635.5, SCV005198223.1 internal data communication), including confirmed in trans with the same pathogenic variant in two cases (c.229C>T p.(Arg77Cys), 1.0 pt x2, ClinVar SCV000941635.5, SCV005198223.1 internal data communication) (PP4, PM3_Strong). It has also been reported in a homozygous state in an individual undergoing clinical genome sequencing for suspected rare disease but without phenotype details provided (PMID: 33726816). The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003623 (33/91090 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.787, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). In addition, another missense variant at the same codon, c.662G>C p.(Arg221Pro), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the 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 2.0.0; 10/28/2025): PP4, PM3_Strong, PP3, PM5_Supporting.
Met criteria codes
PP4
At least one patient with this variant and a second SGCA variant had a clinical suspicion of limb girdle muscular dystrophy (PP4). Alonso-Perez case has <30% protein expression but limited phenotype info and can't confidently confirm screening of other sarcoglycan genes.
PP3
The computational predictor REVEL gives a score of 0.787, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3).
PM3_Strong
This variant has been identified in at least eight individuals with a clinical suspicion of limb girdle muscular dystrophy (PMID: 35416532, 28403181, 30564623, 32528171, 32875335; LOVD SGCA_000169; John Walton Muscular Dystrophy Research Centre internal data communication; ClinVar SCV000941635.5, SCV005198223.1 internal data communication), including confirmed in trans with the same pathogenic variant in two cases (c.229C>T p.(Arg77Cys), 1.0 pt x2, ClinVar SCV000941635.5, SCV005198223.1 internal data communication) (PM3_Strong). It has also been reported in a homozygous state in an individual undergoing clinical genome sequencing for suspected rare disease but without phenotype details provided (PMID: 33726816). Ek et al. (2023) is cited in ClinVar, but I could not find this variant in the text or supplementary table. potential additional pts: 2 pts needed for Very Strong c.226C>T (p.Leu76Phe): unconfirmed phase, not on priority list; LP/P in ClinVar, at least 2 other lit reports (PMID: 24742800, 30345904) (0.5 pts if independently P) c.197T>A (p.Leu66His): unconfirmed phase, on priority list: P/LP/VUS in ClinVar, at least 2 other lit reports (PMID: 31069529, 33552634) (1.0 pt if independently P; 2 cases) p.(Arg34Cys): unconfirmed phase, independently LP (0.25 pts) c.488dup p.(Leu164ThrfsTer27): unconfirmed phase, not on priority list; expected P, at least 1 other lit report (PMID: 18996010) (0.5 pts if independently P) c.312G>A (p.Glu104=): unconfirmed phase, not on priority list; VUS in ClinVar, ablates canonical donor (PP3) (may stay VUS)
PM5_Supporting
Another missense variant at the same codon, c.662G>C (p.Arg221Pro), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003623 (33/91090 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met).
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Grpmax FAF 0.0002648
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Grpmax FAF 0.0002648
Curation History
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