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
Consequence
NM_000232.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SGCB | NM_000232.5 | c.699_702delCATT | p.Phe233fs | frameshift_variant | 5/6 | ENST00000381431.10 | NP_000223.1 | |
SGCB | XM_047416074.1 | c.489_492delCATT | p.Phe163fs | frameshift_variant | 4/5 | XP_047272030.1 | ||
SGCB | XM_047416075.1 | c.402_405delCATT | p.Phe134fs | frameshift_variant | 4/5 | XP_047272031.1 | ||
SGCB | XM_047416076.1 | c.402_405delCATT | p.Phe134fs | frameshift_variant | 4/5 | XP_047272032.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Jan 08, 2025 | 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
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 18, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at