rs1057516515

Variant names:

• chr4-52028018-TAATG-T
• rs1057516515
• NM_000232.5:c.699_702delCATT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP1 PP4 PM2_Supporting PM3 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000232.5: c.699_702del p.(Phe233LeufsTer16) variant in SGCB is a frameshift variant that may cause loss of function of the protein; the resulting transcript is predicted to escape nonsense mediated decay but remove >10% of the protein (PVS1_Strong). This variant has been detected in at least two unrelated individuals with autosomal recessive limb girdle muscular dystrophy, including confirmed in trans with a likely pathogenic or pathogenic variant (c.377_384dup, 1 pt, PMID:25862795) and in a homozygous state (0.25 pts, PMID:25862795) (PM3). At least one patient with this variant and a second SGCB variant displayed progressive limb girdle muscle weakness as well as absent expression of beta-sarcoglycan protein, which is highly specific for SGCB-related LGMD; however, the presence of potentially diagnostic variants in all of the other sarcoglycan genes was not ruled out (PP4; PMID:12868499, 25862795, 9032047). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID:25862795) and is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). 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, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16040953/MONDO:0015152/184

• Frequency: Genomes: not found (cov: 33)
• Consequence: SGCB NM_000232.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.18
• Publications: 0 publications found

Genes affected

SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

SGCB Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2E

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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
SGCB	NM_000232.5	c.699_702delCATT	p.Phe233LeufsTer16	frameshift_variant	Exon 5 of 6	ENST00000381431.10	NP_000223.1
SGCB	NM_001440519.1	c.489_492delCATT	p.Phe163LeufsTer16	frameshift_variant	Exon 4 of 5		NP_001427448.1
SGCB	NM_001440520.1	c.402_405delCATT	p.Phe134LeufsTer16	frameshift_variant	Exon 6 of 7		NP_001427449.1
SGCB	XM_047416076.1	c.402_405delCATT	p.Phe134LeufsTer16	frameshift_variant	Exon 4 of 5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.699_702delCATT	p.Phe233LeufsTer16	frameshift_variant	Exon 5 of 6	1	NM_000232.5	ENSP00000370839.6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

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_000232.5: c.699_702del p.(Phe233LeufsTer16) variant in SGCB is a frameshift variant that may cause loss of function of the protein; the resulting transcript is predicted to escape nonsense mediated decay but remove >10% of the protein (PVS1_Strong). This variant has been detected in at least two unrelated individuals with autosomal recessive limb girdle muscular dystrophy, including confirmed in trans with a likely pathogenic or pathogenic variant (c.377_384dup, 1 pt, PMID: 25862795) and in a homozygous state (0.25 pts, PMID: 25862795) (PM3). At least one patient with this variant and a second SGCB variant displayed progressive limb girdle muscle weakness as well as absent expression of beta-sarcoglycan protein, which is highly specific for SGCB-related LGMD; however, the presence of potentially diagnostic variants in all of the other sarcoglycan genes was not ruled out (PP4; PMID: 12868499, 25862795, 9032047). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in one affected family member (PP1; PMID: 25862795) and is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). 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, PM2_Supporting. -

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:1

Feb 18, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057516515; hg19: chr4-52894184;