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]
  • No ClinVar Id was directly found from the curated document
  • No CSPEC computed assertion could be determined for this classification!

Variant: NR_135553.2:n.649C>T

CA400180431

Gene: SGCA (HGNC:6442)
Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)
Inheritance Mode: Autosomal recessive inheritance
UUID: 48c0b2b6-40e6-4b99-a6a5-d6bdc5b64264
Approved on: 2026-04-29
Published on: 2026-05-07

HGVS expressions

NR_135553.2:n.649C>T
NC_000017.11:g.50169120C>T
CM000679.2:g.50169120C>T
NC_000017.10:g.48246481C>T
CM000679.1:g.48246481C>T
NC_000017.9:g.45601480C>T
NG_008889.1:g.8116C>T
ENST00000504073.2:c.597+16C>T
ENST00000511303.6:n.309+548C>T
ENST00000512526.2:c.575+548C>T
ENST00000682109.1:c.493C>T
ENST00000683226.1:n.323C>T
ENST00000683294.1:c.613C>T
ENST00000262018.8:c.613C>T
ENST00000262018.7:c.613C>T
ENST00000344627.10:c.584+548C>T
ENST00000502555.5:c.*272C>T
ENST00000504073.1:c.64+16C>T
ENST00000511303.5:c.305+548C>T
ENST00000512526.1:c.419+548C>T
ENST00000513821.5:c.613C>T
ENST00000513942.5:n.375+548C>T
NM_000023.2:c.613C>T
NM_001135697.1:c.584+548C>T
NM_000023.3:c.613C>T
NM_001135697.2:c.584+548C>T
NR_135553.1:n.669C>T
NM_000023.4:c.613C>T
NM_001135697.3:c.584+548C>T
More

Pathogenic

Met criteria codes 6
PM3_Supporting PS3_Moderate PP3 PM5_Supporting PP4_Strong PM2_Supporting
Not Met criteria codes 1
PP1

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.613C>T variant in SGCA is a missense variant predicted to cause substitution of proline by serine at amino acid 205, p.(Pro205Ser). This variant has been detected in at least two individuals with limb girdle muscular dystrophy (Newcastle University, GRASP-LGMD Consortium internal data communication), including in unconfirmed phase with a pathogenic variant in one case (c.229C>T p.(Arg77Cys), 0.5 pt, Newcastle University internal data communication) (PM3_Supporting). At least one patient with this variant and a second presumed diagnostic SGCA variant displayed both progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong; Newcastle University, GRASP-LGMD Consortium internal data communication). The variant has been reported to segregate with limb-girdle muscular dystrophy in two affected siblings from one family, but phase was not confirmed (Newcastle University internal data communication). The Grpmax variant allele frequency is 0.000011 in gnomAD v4.1.1 (1/91088 South Asian alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion. An in vitro assay in a heterologous cell system has demonstrated that this variant disrupts membrane localization of the sarcoglycan complex (PS3_Moderate; Washington University internal data communication). In addition, the computational predictor REVEL gives a score of 0.815, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). Another missense variant affecting the same codon, c.614C>A p.(Pro205His), has also 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 Pathogenic for autosomal recessive limb-girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specification guidelines v2.0.0; 04/29/2026): PM3_Supporting, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5_Supporting.
Met criteria codes
PM3_Supporting
This variant has been detected in at least two individuals with limb girdle muscular dystrophy (Newcastle University, GRASP-LGMD Consortium internal data communication), including in unconfirmed phase with a pathogenic variant in one case (c.229C>T p.(Arg77Cys), 0.5 pt, Newcastle University internal data communication) (PM3_Supporting). GnomAD Variant co-Occurrence cannot be implemented as variant c.265C>T is not present in GnomAD v.2. The second (GRASP) patient has c.265C>T p.(Leu89Phe), which is a VUS without the PP4_Strong evidence from this case.
PS3_Moderate
In vitro assay in an heterologous cell system has demonstrated that this variant disrupts membrane localization of the sarcoglycan complex (PS3_Moderate, Washington University internal data). Variant was tested by Gabe Haller's team using their previously reported approach for SGCB variants. The assay has been clinically validated with over 11 control variants. The variant presented a score <-0.5 (-0.71), which is the threshold for non-functional variants that was used for SGCB. Score -1.88 in complementary assay done in the Lek lab at Yale. (concordant)
PP3
The computational predictor REVEL gives a score of 0.815, which is above the threshold of 0.7, evidence that correlates with impact to SGCA function (PP3). SpliceAI: 0.100
PM5_Supporting
Another missense variant affecting the same codon, c.614C>A p.(Pro205His), has been classified as likely pathogenic for autosomal recessive limb-girdle muscular dystrophy by the ClinGen LGMD VCEP (PM5_Supporting). NM_000023.4(SGCA):c.614C>A p.(Pro205His) SpliceAI: 0.0800 LP without use of PM5 The REVEL score for the curated variant is >0.7, and the SpliceAI scores for both curated and comparison variant are <0.5
PP4_Strong
At least one patient with this variant and a second presumed diagnostic SGCA variant displayed both progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong; Newcastle University, GRASP-LGMD Consortium internal data communication).
PM2_Supporting
The Grpmax variant allele frequency is 0.000011 in gnomAD v4.1.1 (1/91088 South Asian alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion.
Not Met criteria codes
PP1
The variant has been reported to segregate with limb-girdle muscular dystrophy in two affected siblings from one family, but phase was not confirmed (Newcastle University internal data communication).
Curation History
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