Evidence Repository - Clinical Genome Resources

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Variant: NM_001130987.2(DYSF):c.4989del (p.Glu1663fs)

CA533262859

1300185 (ClinVar)

Gene: DYSF (HGNC:8291)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: 14f74d3c-69bd-4b31-8825-d8129650e299

Approved on: 2025-08-14

Published on: 2025-09-05

HGVS expressions

NM_001130987.2:c.4989del

NM_001130987.2(DYSF):c.4989del (p.Glu1663fs)

NC_000002.12:g.71660637del

CM000664.2:g.71660637del

NC_000002.11:g.71887767del

CM000664.1:g.71887767del

NC_000002.10:g.71741275del

NG_008694.1:g.212015del

ENST00000698057.1:c.2403del

ENST00000698058.1:c.1620del

ENST00000698059.1:c.1728del

ENST00000258104.8:c.4872del

ENST00000410020.8:c.4989del

ENST00000258104.7:c.4872del

ENST00000394120.6:c.4875del

ENST00000409366.5:c.4938del

ENST00000409582.7:c.4986del

ENST00000409651.5:c.4968del

ENST00000409744.5:c.4896del

ENST00000409762.5:c.4923del

ENST00000410020.7:c.4989del

ENST00000410041.1:c.4926del

ENST00000413539.6:c.4965del

ENST00000429174.6:c.4935del

ENST00000479049.6:n.1757del

NM_001130455.1:c.4875del

NM_001130976.1:c.4830del

NM_001130977.1:c.4893del

NM_001130978.1:c.4935del

NM_001130979.1:c.4965del

NM_001130980.1:c.4923del

NM_001130981.1:c.4986del

NM_001130982.1:c.4968del

NM_001130983.1:c.4938del

NM_001130984.1:c.4896del

NM_001130985.1:c.4926del

NM_001130986.1:c.4833del

NM_001130987.1:c.4989del

NM_003494.3:c.4872del

NM_001130455.2:c.4875del

NM_001130976.2:c.4830del

NM_001130977.2:c.4893del

NM_001130978.2:c.4935del

NM_001130979.2:c.4965del

NM_001130980.2:c.4923del

NM_001130981.2:c.4986del

NM_001130982.2:c.4968del

NM_001130983.2:c.4938del

NM_001130984.2:c.4896del

NM_001130985.2:c.4926del

NM_001130986.2:c.4833del

NM_003494.4:c.4872del

Pathogenic

PP4_Strong PM3 PM2_Supporting PVS1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.4872delG p.(Glu1624AspfsTer10) variant in DYSF, which is also known as NM_001130987.2: c.4989del (p.Glu1663AspfsTer10), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 45/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least 13 unrelated patients with phenotypes consistent with LGMD in a homozygous state in all individuals, with reported consanguinity in at least one family (1.0 pt, PMID: 10825360, 35723113, 17698709) (PM3). Many of these families were Jewish and from Libya. At least one of these individuals displayed muscle weakness and reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 17698709; PP4_Strong). The highest population frequency of this variant in gnomAD v4.1.0 is 0.00001335 in the African/African American population (1/74922 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (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; 08/14/2025): PVS1, PP4_Strong, PM3, PM2_Supporting.

PP4_Strong

At least one of these individuals displayed muscle weakness and reduced or absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PMID: 17698709; PP4_Strong).

PM3

This variant has been reported in at least 13 unrelated patients with phenotypes consistent with LGMD and was identified in a homozygous state in all individuals, with reported consanguinity in at least one family (1.0 pt, PMID: 10825360, 35723113, 17698709) (PM3). Many of these families were Jewish and from Libya.

PM2_Supporting

The highest population frequency of this variant in gnomAD v4.1.0 is 0.00001335 in the African/African American population (1/74922 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). Criterion also met if FAF used: 0.000009455 (the upper threshold of the 95% CI of 5/1111868 European (non-Finnish) exome chromosomes)

PVS1

The NM_003494.4: c.4872del p.(Glu1624AspfsTer10) variant in DYSF, which is also known as NM_001130987.2: c.4989del (p.Glu1663AspfsTer10), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 45/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). deletion is in exon 44 but premature stop is in exon 45

Curation History

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