NM_003494.4:c.4609del

CA2573052014

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: abfea3c9-c81e-41c2-be60-7c399ef7a867

Approved on: 2025-08-19

Published on: 2025-09-05

HGVS expressions

NM_003494.4:c.4609del
NC_000002.12:g.71656261del
CM000664.2:g.71656261del
NC_000002.11:g.71883391del
CM000664.1:g.71883391del
NC_000002.10:g.71736899del
NG_008694.1:g.207639del
ENST00000698057.1:c.2140del
ENST00000698058.1:c.1357del
ENST00000698059.1:c.1465del
ENST00000258104.8:c.4609del
ENST00000410020.8:c.4726del
ENST00000258104.7:c.4609del
ENST00000394120.6:c.4612del
ENST00000409366.5:c.4675del
ENST00000409582.7:c.4723del
ENST00000409651.5:c.4705del
ENST00000409744.5:c.4633del
ENST00000409762.5:c.4660del
ENST00000410020.7:c.4726del
ENST00000410041.1:c.4663del
ENST00000413539.6:c.4702del
ENST00000429174.6:c.4672del
ENST00000479049.6:n.1494del
NM_001130455.1:c.4612del
NM_001130976.1:c.4567del
NM_001130977.1:c.4630del
NM_001130978.1:c.4672del
NM_001130979.1:c.4702del
NM_001130980.1:c.4660del
NM_001130981.1:c.4723del
NM_001130982.1:c.4705del
NM_001130983.1:c.4675del
NM_001130984.1:c.4633del
NM_001130985.1:c.4663del
NM_001130986.1:c.4570del
NM_001130987.1:c.4726del
NM_003494.3:c.4609del
NM_001130987.2:c.4726del
NM_001130455.2:c.4612del
NM_001130976.2:c.4567del
NM_001130977.2:c.4630del
NM_001130978.2:c.4672del
NM_001130979.2:c.4702del
NM_001130980.2:c.4660del
NM_001130981.2:c.4723del
NM_001130982.2:c.4705del
NM_001130983.2:c.4675del
NM_001130984.2:c.4633del
NM_001130985.2:c.4663del
NM_001130986.2:c.4570del

Pathogenic

• Met criteria codes: PP4 PVS1 PM2_Supporting

• Not Met criteria codes: PM3

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 2.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.4609del p.(Glu1537LysfsTer5) variant in DYSF, which is also known as NM_001130987.2: c.4726del p.(Glu1576LysfsTer5), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 42/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported with a second presumed diagnostic DYSF variant in at least two individuals with progressive limb girdle muscle weakness (PMID: 34559919; LOVD Individuals #00375983, #00376095) (PP4). It is also absent from gnomAD v4.1.0 (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 2.0.0; 08/19/2025): PVS1, PP4, PM2_Supporting.

Met criteria codes

• PP4: This variant has been reported with a second presumed diagnostic DYSF variant in at least two individuals with progressive limb girdle muscle weakness (PMID: 34559919; LOVD Individuals #00375983, #00376095) (PP4).
• PVS1: The NM_003494.4: c.4609del p.(Glu1537LysfsTer5) variant in DYSF, which is also known as NM_001130987.2: c.4726del p.(Glu1576LysfsTer5), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 42/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• PM3: This variant has been reported in at least two individuals with features consistent with LGMD (PMID: 34559919, LOVD DYSF_001338). Not scored because other variant not curated or depends on this case for LP classification, and this code not needed to reach P classification