rs781760379

Variant names:

• chr13-23203852-T-C
• rs781760379
• NM_000231.3:c.158T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP4_Strong PM3 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000231.3: c.158T>C variant in SGCG is a missense variant predicted to cause substitution of leucine by proline at amino acid 53 (p.Leu53Pro). This variant has been detected in at least three individuals with autosomal recessive limb girdle muscular dystrophy (PMID:30564623, 18996010), including in a homozygous state in two patients (1.0 pt, PMID:18996010) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced expression of gamma sarcoglycan protein in skeletal muscle, which is highly specific for SGCG-related LGMD (PP4_Strong; PMID:18996010). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113696 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). The computational predictor REVEL gives a score of 0.98, which exceeds the threshold of ≥0.70, evidence that correlates with impact to SGCG function (PP3). 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; 01/08/2025): PP4_Strong, PM3, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10606508/MONDO:0015152/185

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SGCG NM_000231.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.26
• Publications: 2 publications found

Genes affected

SGCG (HGNC:10809): (sarcoglycan gamma) This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

SGCG Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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_000231.3. 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
	SGCG	NM_000231.3	MANE Select	c.158T>C	p.Leu53Pro	missense	Exon 2 of 8	NP_000222.2	Q13326
	SGCG	NM_001378244.1		c.212T>C	p.Leu71Pro	missense	Exon 2 of 8	NP_001365173.1
	SGCG	NM_001378245.1		c.158T>C	p.Leu53Pro	missense	Exon 3 of 9	NP_001365174.1	Q13326

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCG	ENST00000218867.4	TSL:1 MANE Select	c.158T>C	p.Leu53Pro	missense	Exon 2 of 8	ENSP00000218867.3	Q13326
	SGCG	ENST00000942469.1		c.158T>C	p.Leu53Pro	missense	Exon 2 of 9	ENSP00000612528.1
	SGCG	ENST00000876364.1		c.158T>C	p.Leu53Pro	missense	Exon 3 of 9	ENSP00000546423.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251386 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461506 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111666

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2C (3)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Loss of stability (P = 0.0189)
MVP		0.96
MPC		0.51
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.99
Mutation Taster		=2/98	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: rs781760379; hg19: chr13-23777991;