Variant: NM_003494.4:c.237-159_342+1237del

CA2837582287

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 735f6622-9a68-41a3-bf8d-e6f9652bbf13

Approved on: 2025-04-11

Published on: 2025-05-16

HGVS expressions

NM_003494.4:c.237-159_342+1237del
NC_000002.12:g.71503055_71504556del
CM000664.2:g.71503055_71504556del
NC_000002.11:g.71730185_71731686del
CM000664.1:g.71730185_71731686del
NC_000002.10:g.71583693_71585194del
NG_008694.1:g.54433_55934del
ENST00000258104.8:c.237-159_342+1237del
ENST00000410020.8:c.240-159_345+1237del
ENST00000258104.7:c.237-159_342+1237del
ENST00000394120.6:c.240-159_345+1237del
ENST00000409366.5:c.240-159_345+1237del
ENST00000409582.7:c.237-159_342+1237del
ENST00000409651.5:c.240-159_345+1237del
ENST00000409744.5:c.240-159_345+1237del
ENST00000409762.5:c.237-159_342+1237del
ENST00000410020.7:c.240-159_345+1237del
ENST00000410041.1:c.240-159_345+1237del
ENST00000413539.6:c.237-159_342+1237del
ENST00000429174.6:c.237-159_342+1237del
NM_001130455.1:c.240-159_345+1237del
NM_001130976.1:c.237-159_342+1237del
NM_001130977.1:c.237-159_342+1237del
NM_001130978.1:c.237-159_342+1237del
NM_001130979.1:c.237-159_342+1237del
NM_001130980.1:c.237-159_342+1237del
NM_001130981.1:c.237-159_342+1237del
NM_001130982.1:c.240-159_345+1237del
NM_001130983.1:c.240-159_345+1237del
NM_001130984.1:c.240-159_345+1237del
NM_001130985.1:c.240-159_345+1237del
NM_001130986.1:c.240-159_345+1237del
NM_001130987.1:c.240-159_345+1237del
NM_003494.3:c.237-159_342+1237del
NM_001130987.2:c.240-159_345+1237del
NM_001130455.2:c.240-159_345+1237del
NM_001130976.2:c.237-159_342+1237del
NM_001130977.2:c.237-159_342+1237del
NM_001130978.2:c.237-159_342+1237del
NM_001130979.2:c.237-159_342+1237del
NM_001130980.2:c.237-159_342+1237del
NM_001130981.2:c.237-159_342+1237del
NM_001130982.2:c.240-159_345+1237del
NM_001130983.2:c.240-159_345+1237del
NM_001130984.2:c.240-159_345+1237del
NM_001130985.2:c.240-159_345+1237del
NM_001130986.2:c.240-159_345+1237del

Pathogenic

• Met criteria codes: PP4_Strong PM2_Supporting PVS1 PM3_Supporting

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DYSF Version 1.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NC_000002.12: g.71503055_71504556del variant (GRCh38) is an intragenic deletion with intronic breakends that encompasses exon 4 of the DYSF gene, NM_003494.4: c.237_342del. RNAseq analysis has demonstrated that this variant results in skipping of exon 4, which is expected to lead to a frameshift, premature truncation (p.Phe80ProfsTer36), and nonsense mediated decay in a gene for which loss of function is a known disease mechanism (PMID: 36983702; PVS1_RNA). This variant has been reported in unknown phase with a pathogenic variant in an individual with LGMD (NM_003494.4: c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 36983702) (PM3_Supporting). This patient displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong). A similar deletion has also been reported in ClinVar (SCV003791359.2). No similar deletions are observed in gnomAD SVs or CNVs v4.1.0 or in the Database of Genomic Variants (PMID: 24174537; PM2_Supporting). In summary, this variant meets the criteria to be classified as 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; 04/11/2025): PVS1_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting.

Met criteria codes

• PP4_Strong: At least one individual with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong).
• PM2_Supporting: No similar deletions are observed in gnomAD SVs v4.1.0 and v2.1 or in the Database of Genomic Variants PMID: 24174537 (PM2_Supporting).
• PVS1: The NC_000002.11:g.71730185_71731686del variant is a deletion that encompasses exon 4 of the DYSF gene, NM_003494.4: c.237_342del. RNAseq analysis has demonstrated that skipping of exon 4 leads to a frameshift and premature truncation, p.Phe80ProfsTer36 (PVS1_RNA).
• PM3_Supporting: This variant has been reported in unknown phase with a pathogenic variant in an individual with LGMD (c.5698_5699del p.(Ser1900GlnfsTer14), 0.5 pts, PMID: 36983702) (PM3_Supporting).