13-23295429-CT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP1_ModeratePP4PM3PVS1_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: đť‘“ 0.000066 ( 0 hom., cov: 33)
Exomes đť‘“: 0.000053 ( 0 hom. )

Consequence

SGCG
NM_000231.3 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 2.68
Variant links:
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]

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ACMG classification

Classification made for transcript

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
SGCGNM_000231.3 linkc.525delT p.Phe175LeufsTer20 frameshift_variant Exon 6 of 8 ENST00000218867.4 NP_000222.2 Q13326

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SGCGENST00000218867.4 linkc.525delT p.Phe175LeufsTer20 frameshift_variant Exon 6 of 8 1 NM_000231.3 ENSP00000218867.3 Q13326
SACSENST00000683210.1 linkc.2186-6187delA intron_variant Intron 9 of 9 ENSP00000506739.1 A0A804HHS6

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152134
Hom.:
0
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

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

May 22, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189243 / PMID: 7481775). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

- -

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

- -

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). -

Mar 14, 2024
Baylor Genetics
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

- -

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. -

Feb 22, 2017
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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

- -

Aug 01, 2019
Section for Clinical Neurogenetics, University of TĂĽbingen
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) -

Aug 26, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

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

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786204786; hg19: chr13-23869568; API