Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001130987.2(DYSF):c.5298del (p.Glu1766fs)

CA2573135907

1455030 (ClinVar)

Gene: DYSF (HGNC:8291)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: 7e3805af-ba9f-478e-961f-9385ace168f2

Approved on: 2025-02-25

Published on: 2025-03-07

HGVS expressions

NM_001130987.2(DYSF):c.5298del (p.Glu1766fs)

NM_001130987.2:c.5298del

NC_000002.12:g.71665285del

CM000664.2:g.71665285del

NC_000002.11:g.71892415del

CM000664.1:g.71892415del

NC_000002.10:g.71745923del

NG_008694.1:g.216663del

ENST00000698057.1:c.2712del

ENST00000698058.1:c.1929del

ENST00000698059.1:c.2037del

ENST00000258104.8:c.5181del

ENST00000410020.8:c.5298del

ENST00000258104.7:c.5181del

ENST00000394120.6:c.5184del

ENST00000409366.5:c.5247del

ENST00000409582.7:c.5295del

ENST00000409651.5:c.5277del

ENST00000409744.5:c.5205del

ENST00000409762.5:c.5232del

ENST00000410020.7:c.5298del

ENST00000410041.1:c.5235del

ENST00000413539.6:c.5274del

ENST00000429174.6:c.5244del

ENST00000479049.6:n.2066del

NM_001130455.1:c.5184del

NM_001130976.1:c.5139del

NM_001130977.1:c.5202del

NM_001130978.1:c.5244del

NM_001130979.1:c.5274del

NM_001130980.1:c.5232del

NM_001130981.1:c.5295del

NM_001130982.1:c.5277del

NM_001130983.1:c.5247del

NM_001130984.1:c.5205del

NM_001130985.1:c.5235del

NM_001130986.1:c.5142del

NM_001130987.1:c.5298del

NM_003494.3:c.5181del

NM_001130455.2:c.5184del

NM_001130976.2:c.5139del

NM_001130977.2:c.5202del

NM_001130978.2:c.5244del

NM_001130979.2:c.5274del

NM_001130980.2:c.5232del

NM_001130981.2:c.5295del

NM_001130982.2:c.5277del

NM_001130983.2:c.5247del

NM_001130984.2:c.5205del

NM_001130985.2:c.5235del

NM_001130986.2:c.5142del

NM_003494.4:c.5181del

Pathogenic

PM3 PVS1 PM2_Supporting PP4_Strong

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.5181del p.(Glu1727AspfsTer7) variant in DYSF, which is also known as NM_001130987.2: c.5298del (p.Glu1766AspfsTer7), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 46/55, 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 two individuals with clinical signs of limb girdle muscular dystrophy, including in a homozygous state (0.5 pts, PMID: 29970176) and confirmed in trans with a likely pathogenic or pathogenic variant (c.1668_1669insGTT p.(Leu556_Leu557insVal), 1.0 pt, PMID: 36983702) (PM3). At least one patient with this variant displayed progressive weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702). The highest population minor allele frequency is 0.0000008474 (1/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (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; 02/25/2025): PVS1, PM3, PP4_Strong, PM2_Supporting.

PM3

This variant has been reported in at least two individuals with clinical signs of limb girdle muscular dystrophy, including in a homozygous state (0.5 pts, PMID: 29970176) and confirmed in trans with a likely pathogenic or pathogenic variant (c.1668_1669insGTT p.(Leu556_Leu557insVal), 1.0 pt, PMID: 36983702) (PM3). Note that the homozygous individual was also homozygous for c.5626G>A p.(Asp1876Asn), which can be classified as Benign based on allele frequency (BA1). c.1668_1669insGTT can be classified as at least LP without this observation

PVS1

PM2_Supporting

The highest population minor allele frequency for this variant is 0.0000008474 (1/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PP4_Strong

At least one patient with this variant displayed progressive weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702). Rufibach et al. 2023 (PMID: 36983702) JF358: progressive proximal and distal weakness with initial calf hypertrophy that turned into atrophy, muscle biopsy showed dystrophic features, elevated CK. disease range dysferlin by blood monocyte assay. c.1668_1669insGTT p.(Leu556_Leu557insVal) in trans (P by VCEP)

Curation History

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