rs28933693
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3_StrongPS3_SupportingPP1_StrongPP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000023.4: c.229C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 77 (p.Arg77Cys). This variant has been detected in at least 12 individuals with symptoms of limb girdle muscular dystrophy. Of those individuals, two were confirmed compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.850C>T, 2 pts, PMID:12566530, LOVD Individual #0000223892), and at least two were homozygous for the variant (1 pt, PMID:12566530, 23989969, 7663524, 37628638) (PM3_Strong). The variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in 10 affected family members from five families (PP1_Strong; LOVD Individual #0000223892, PMID:12566530, 7663524). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PMID:7663524; PP4) (capped with PP1_Strong). The filtering allele frequency of this variant is 0.0004392 (the lower threshold of the 95% CI of 62/112872 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is lower than the ClinGen LGMD VCEP threshold (>0.0009) for BS1 (BS1, PM2_Supporting not met). In vitro assays have demonstrated this variant disrupts membrane localization of the sarcoglycan protein complex (PMID:18535179; PS3_Supporting), and the computational predictor REVEL gives a score of 0.95, which exceeds the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). 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 (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3_Strong, PP1_Strong, PP4, PP3, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120427/MONDO:0015152/189
Frequency
Consequence
NM_000023.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SGCA | NM_000023.4 | c.229C>T | p.Arg77Cys | missense_variant | Exon 3 of 10 | ENST00000262018.8 | NP_000014.1 | |
| SGCA | NM_001135697.3 | c.229C>T | p.Arg77Cys | missense_variant | Exon 3 of 8 | NP_001129169.1 | ||
| SGCA | NR_135553.2 | n.265C>T | non_coding_transcript_exon_variant | Exon 3 of 9 |
Ensembl
Frequencies
GnomAD3 genomes 0.000434 AC: 66AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000460 AC: 115AN: 250208Hom.: 0 AF XY: 0.000443 AC XY: 60AN XY: 135374
GnomAD4 exome AF: 0.000473 AC: 692AN: 1461648Hom.: 0 Cov.: 32 AF XY: 0.000433 AC XY: 315AN XY: 727130
GnomAD4 genome 0.000433 AC: 66AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74468
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:15
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NM_000023.2(SGCA):c.229C>T(R77C) is classified as pathogenic in the context of alpha-sarcoglycanopathy. Sources cited for classification include the following: PMID 15736300, 18252745, 9192266 and 18996010. Classification of NM_000023.2(SGCA):c.229C>T(R77C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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The homozgous p.Arg77Cys variant was identified by our study in one individual with Limb-Girdle Muscular Dystrophy. The p.Arg77Cys variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -
This variant was classified as: Pathogenic. This variant was detected in homozygous state. -
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 77 of the SGCA protein (p.Arg77Cys). This variant is present in population databases (rs28933693, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 2D (PMID: 7663524, 9032047, 9153448, 9192266, 15298081, 18285821, 18421900, 21856579, 25135358). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9437). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGCA protein function. Experimental studies have shown that this missense change affects SGCA function (PMID: 16787395, 18252745, 22095924). For these reasons, this variant has been classified as Pathogenic. -
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The c.229C>T (p.Arg77Cys) missense variant in the SGCA gene is the most common pathogenic variant reported in individuals affected with autosomal recessive Limb-girdle muscular dystrophy, type 2D (Piccolo et al., 1995; Carrié et al., 1997; Hackman et al., 2005). This variant is located within a mutational hotspot with variants in exon 3 accounting for up to 46% of the affected alleles (Carrié et al., 1997). This variant has been shown to co-segregate with disease in multiple families (Bueno et al., 1995; Kawai et al., 1995). Functional studies have shown this variant results in improper localization of the protein with its retention in the ER as opposed to the plasma membrane (Bartoli et al., 2008). The c.229C>T variant has been reported at low frequency in the control population databases (Exome Sequencing Project [ESP] = 0.081%, 1000 Genomes = 0.3%, and ExAC = 0.154%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.53; CADD = 26.5; PolyPhen = 1; SIFT = 0), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.229C>T (p.Arg77Cys) as a recessive Pathogenic variant for Limb-girdle muscular dystrophy, type 2D. -
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The p.Arg77Cys variant in SGCA is the most common pathogenic variant in limb girdle muscular dystrophy type 2D (LGMD2D) having been reported in >20 homozygous or compound heterozygous individuals with LGMD2D and segregating in at least 4 affected family members (Bueno 1995 PMID: 8528203, Carrie 1997 PMID: 9192266, Boito 2005 PMID: 12746421, Hackman 2005 PMID: 15736300, Tetreault 2011 PMID: 21856579, Fayssoil 2016 PMID: 21856579, Avila De Salman 2007 PMID: 18421900, Walter 2004 PMID: 15298081, Stehlíková 2014 PMID: 25135358, Trabelsi 2008 PMID: 18285821, Duggan 1997 PMID: 9032047, Piccolo 1995 PMID: 7663524, Eymard 1997 PMID: 9153448). This variant has also been reported in ClinVar (Variation ID 9437) and has been identified in 0.18% (47/24978) of Finnish chromosomes and in 0.05% (69/128290) of European chromosomes by gnomAD (http://gnomAD.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies provide some evidence that this variant impacts protein function by trapping the protein in the endoplasmic reticulum where it is ultimately degraded (Bartoli 2008 PMID: 18252745, Soheili 2012 PMID: 22095924, Gastaldello 2008 PMID: 18535179, Draviam 2006 PMID: 16787395). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb girdle muscular dystrophy type 2D. ACMG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PP1_Moderate, PP3. -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.046%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16787395, 18252745, 22095924). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009437 /PMID: 8528203). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:9
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The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). In multiple individuals with LGMD, this variant has been seen with a single recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16787395, 18252745) -
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Published functional studies demonstrate a damaging effect: absence of the protein at the cell membrane (Draviam et al., 2006; Bartoli et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11391490, 27297959, 27120200, 26934379, 26944168, 31407473, 18421900, 21856579, 22995991, 23989969, 8528203, 7663524, 7657792, 18252745, 22095924, 26916285, 15298081, 24626787, 9436428, 18252746, 9845765, 30919934, 31589614, 32528171, 34106991, 33726816, 15736300, 16787395) -
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Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2
Variant summary: SGCA c.229C>T (p.Arg77Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250208 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00046 vs 0.002), allowing no conclusion about variant significance. c.229C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and has shown to co-segregate with disease in multiple families (examples, Moreira_2003, Tetreault_2011, Vainzof_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of SGCA levels of WT in HER911 cells (Carotti_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29351619, 12566530, 21856579, 10385046). ClinVar contains an entry for this variant (Variation ID: 9437, PATH). Based on the evidence outlined above, the variant was classified as pathogenic. -
The NM_000023.4: c.229C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 77 (p.Arg77Cys). This variant has been detected in at least 12 individuals with symptoms of limb girdle muscular dystrophy. Of those individuals, two were confirmed compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.850C>T, 2 pts, PMID: 12566530, LOVD Individual #0000223892), and at least two were homozygous for the variant (1 pt, PMID: 12566530, 23989969, 7663524, 37628638) (PM3_Strong). The variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in 10 affected family members from five families (PP1_Strong; LOVD Individual #0000223892, PMID: 12566530, 7663524). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PMID: 7663524; PP4) (capped with PP1_Strong). The filtering allele frequency of this variant is 0.0004392 (the lower threshold of the 95% CI of 62/112872 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is lower than the ClinGen LGMD VCEP threshold (>0.0009) for BS1 (BS1, PM2_Supporting not met). In vitro assays have demonstrated this variant disrupts membrane localization of the sarcoglycan protein complex (PMID: 18535179; PS3_Supporting), and the computational predictor REVEL gives a score of 0.95, which exceeds the threshold of ≥0.70, evidence that correlates with impact to SGCA function (PP3). 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 (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM3_Strong, PP1_Strong, PP4, PP3, PS3_Supporting. -
Sarcoglycanopathy Pathogenic:1
Across a selection of the available literature, the SGCA c.229C>T (p.Arg77Cys) variant has been identified in a homozygous state in at least 28 probands and in a compound heterozygous state in at least eight probands with limb-girdle muscular dystrophy (Bueno et al. 1995; Carrie et al. 1997; Boito et al. 2005; Hackman et al. 2005; Teatreault et al. 2011; Fayssoil et al. 2016). The p.Arg77Cys variant was reported in two of 624 controls and is reported at a frequency of 0.001949 in the European (Finnish) population from the Genome Aggregation Database. Functional studies in human cell lines showed that the p.Arg77Cys variant protein does not localize to the cell membrane, results in impaired assembly of the sarcoglycan complex, and is retained in the endoplasmic reticulum (Bartoli et al. 2008; Gastaldello et al. 2008). Based on the collective evidence, the p.Arg77Cys variant is classified as pathogenic for alpha-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Abnormality of the musculature Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at