rs28933693

Variant names:

• chr17-50167653-C-T
• rs28933693
• NM_000023.4:c.229C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PP4 PM3_Strong PP1_Strong PS3_Supporting

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:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:30
• Conservation: PhyloP100: 6.82
• Publications: 68 publications found

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

SGCA Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000253730 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000023.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	NM_000023.4	MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 3 of 10	NP_000014.1	A0A0S2Z4Q1
	SGCA	NM_001135697.3		c.229C>T	p.Arg77Cys	missense	Exon 3 of 8	NP_001129169.1	A0A0S2Z4P8
	SGCA	NR_135553.2		n.265C>T		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.229C>T	p.Arg77Cys	missense	Exon 3 of 10	ENSP00000262018.3	Q16586-1
	SGCA	ENST00000344627.10	TSL:1	c.229C>T	p.Arg77Cys	missense	Exon 3 of 8	ENSP00000345522.6	Q16586-2
	SGCA	ENST00000952408.1		c.319C>T	p.Arg107Cys	missense	Exon 3 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000460 AC: 115 AN: 250208 AF XY: 0.000443

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000473 AC: 692 AN: 1461648 Hom.: 0 Cov.: 32 AF XY: 0.000433 AC XY: 315 AN XY: 727130

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00162 AC: 86 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000513 AC: 570 AN: 1111966

Other (OTH) AF: 0.000348 AC: 21 AN: 60394

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74468

African (AFR) AF: 0.0000963 AC: 4 AN: 41550

American (AMR) AF: 0.000261 AC: 4 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000539 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
16	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2D (16)
9	-	-	not provided (9)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	Limb-girdle muscular dystrophy (1)
1	-	-	Sarcoglycanopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.99
MPC		1.3
ClinPred		0.19	T
GERP RS		4.5
Varity_R		0.62
gMVP		0.92
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28933693; hg19: chr17-48245014;