rs1057516515

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_StrongPM3PP1PP4PM2_Supporting

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

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 9.18
Variant links:
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]

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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.
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/exons MANE Protein UniProt
SGCBNM_000232.5 linkc.699_702delCATT p.Phe233fs frameshift_variant 5/6 ENST00000381431.10 NP_000223.1 Q16585-1Q5U0N0
SGCBXM_047416074.1 linkc.489_492delCATT p.Phe163fs frameshift_variant 4/5 XP_047272030.1
SGCBXM_047416075.1 linkc.402_405delCATT p.Phe134fs frameshift_variant 4/5 XP_047272031.1
SGCBXM_047416076.1 linkc.402_405delCATT p.Phe134fs frameshift_variant 4/5 XP_047272032.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SGCBENST00000381431.10 linkc.699_702delCATT p.Phe233fs frameshift_variant 5/61 NM_000232.5 ENSP00000370839.6 Q16585-1

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
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGenJan 08, 2025The 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
Likely pathogenic, criteria provided, single submitterclinical testingCounsylFeb 18, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1057516515; hg19: chr4-52894184; API