13-23295429-CT-C

Variant names:

• chr13-23295429-CT-C
• rs786204786
• NM_000231.3:c.525delT

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3 PP1_Moderate PP4 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000231.3: c.525del p.(Phe175LeufsTer20) variant in SGCG is a frameshift variant that is predicted to introduce a premature stop codon. The resulting transcript is predicted to escape nonsense mediated decay but truncate >10% of the protein (PVS1_Strong). This variant has been detected in at least five apparently unrelated patients with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least four individuals (1.0 pt, PMID:16616845, 10993494, 18285821, 10942431; ClinVar SCV001164546.1) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). While absent gamma-sarcoglycan protein expression has been reported in the skeletal muscle of patients with this variant, detection may be dependent on the antibody used due to the production of a truncated protein (PMID:10993494, 16616845, 10942431). The variant has been reported to segregate with autosomal recessive LGMD in four affected family members from two families (PP1_Moderate; PMID:10942431, ClinVar SCV001164546.1). The highest minor allele frequency of this variant is 0.0002619 (4/15274 genome chromosomes) in the Admixed American population in gnomAD v3.2.1, which is greater than the VCEP threshold (0.00009) for PM2_Supporting (criterion not met). 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): PVS1_Strong, PM3, PP4, PP1_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA346837/MONDO:0015152/185

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: SGCG NM_000231.3 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 2.68

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]

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCG	NM_000231.3	c.525delT	p.Phe175LeufsTer20	frameshift_variant	Exon 6 of 8	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4	c.525delT	p.Phe175LeufsTer20	frameshift_variant	Exon 6 of 8	1	NM_000231.3	ENSP00000218867.3
SACS	ENST00000683210.1	c.2186-6187delA		intron_variant	Intron 9 of 9			ENSP00000506739.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251462 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1461662 Hom.: 0 Cov.: 30 AF XY: 0.0000536 AC XY: 39 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C Pathogenic:13

Mar 14, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 3.184%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10206677, 10206677, 9654207). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.77 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.88 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001900 / PMID: 10206677).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 9654207).A different missense change at the same codon (p.Asp424Tyr) has been reported to be associated with BTD related disorder (PMID: 33312878). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 22, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Phe175LeufsTer20 variant in SGCG was identified by our study in five individuals (four siblings and one unrelated individual) with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006092% (15/246240) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765500509). Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 175 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SGCG gene is an established disease mechanism in autosomal recessive LGMD. This variant has also been reported in ClinVar (Variation ID: 189243). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple reports in ClinVar. ACMG/AMP Criteria applied: PM2, PVS1, PP1 (Richards 2015). -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe175Leufs*20) in the SGCG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCG are known to be pathogenic (PMID: 18285821). This variant is present in population databases (rs765500509, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 7481775, 12040521, 22240777, 23929688, 24552312). ClinVar contains an entry for this variant (Variation ID: 189243). For these reasons, this variant has been classified as Pathogenic. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe175LeufsX20 variant in SGCG has been reported in many individuals with limb girdle muscular dystrophy type 2C (LGMD2C; Noguchi 1995, Boyden 2010, Herson 2012, Schroder 2014, El Kerch 2014). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 175 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of SGCG function is an established disease mechanism in LGMD2C. In summary, this variant meets our criteria to be classified as pathogenic for LGMD2C in an autosomal recessive manner. -

Aug 12, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 30, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2019

Section for Clinical Neurogenetics, University of Tübingen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:4

Dec 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11693784, 18285821, 22367371, 17994539, 16832103, 23929688, 7481775, 16616845, 15954112, 14678800, 26404900, 25252238, 16916601, 22240777, 24552312, 12040521, 27759885, 30919934, 31130284, 31980526, 31127727, 8900232, 20623375, 19770540, 10942431, 32214227, 25214167, 32528171, 31589614) -

Dec 19, 2014

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. Found in multiple individuals with expected phenotype for this gene. -

Aug 26, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000231.3: c.525del p.(Phe175LeufsTer20) variant in SGCG is a frameshift variant that is predicted to introduce a premature stop codon. The resulting transcript is predicted to escape nonsense mediated decay but truncate >10% of the protein (PVS1_Strong). This variant has been detected in at least five apparently unrelated patients with autosomal recessive limb girdle muscular dystrophy, including in a homozygous state in at least four individuals (1.0 pt, PMID: 16616845, 10993494, 18285821, 10942431; ClinVar SCV001164546.1) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). While absent gamma-sarcoglycan protein expression has been reported in the skeletal muscle of patients with this variant, detection may be dependent on the antibody used due to the production of a truncated protein (PMID: 10993494, 16616845, 10942431). The variant has been reported to segregate with autosomal recessive LGMD in four affected family members from two families (PP1_Moderate; PMID: 10942431, ClinVar SCV001164546.1). The highest minor allele frequency of this variant is 0.0002619 (4/15274 genome chromosomes) in the Admixed American population in gnomAD v3.2.1, which is greater than the VCEP threshold (0.00009) for PM2_Supporting (criterion not met). 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): PVS1_Strong, PM3, PP4, PP1_Moderate. -

SGCG-related congenital myopathy Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1+PM2 -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204786; hg19: chr13-23869568;