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.2948G>A (p.Trp983Ter)

CA347216158

498353 (ClinVar)

Gene: DYSF (HGNC:8291)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: f5831e0f-2289-4e23-a276-552e0ec807d3

Approved on: 2025-07-29

Published on: 2025-08-14

HGVS expressions

NM_001130987.2(DYSF):c.2948G>A (p.Trp983Ter)

NM_001130987.2:c.2948G>A

NC_000002.12:g.71569903G>A

CM000664.2:g.71569903G>A

NC_000002.11:g.71797033G>A

CM000664.1:g.71797033G>A

NC_000002.10:g.71650541G>A

NG_008694.1:g.121281G>A

ENST00000698057.1:c.320G>A

ENST00000258104.8:c.2894G>A

ENST00000410020.8:c.2948G>A

ENST00000258104.7:c.2894G>A

ENST00000394120.6:c.2897G>A

ENST00000409366.5:c.2897G>A

ENST00000409582.7:c.2945G>A

ENST00000409651.5:c.2990G>A

ENST00000409744.5:c.2855G>A

ENST00000409762.5:c.2945G>A

ENST00000410020.7:c.2948G>A

ENST00000410041.1:c.2948G>A

ENST00000413539.6:c.2987G>A

ENST00000429174.6:c.2894G>A

NM_001130455.1:c.2897G>A

NM_001130976.1:c.2852G>A

NM_001130977.1:c.2852G>A

NM_001130978.1:c.2894G>A

NM_001130979.1:c.2987G>A

NM_001130980.1:c.2945G>A

NM_001130981.1:c.2945G>A

NM_001130982.1:c.2990G>A

NM_001130983.1:c.2897G>A

NM_001130984.1:c.2855G>A

NM_001130985.1:c.2948G>A

NM_001130986.1:c.2855G>A

NM_001130987.1:c.2948G>A

NM_003494.3:c.2894G>A

NM_001130455.2:c.2897G>A

NM_001130976.2:c.2852G>A

NM_001130977.2:c.2852G>A

NM_001130978.2:c.2894G>A

NM_001130979.2:c.2987G>A

NM_001130980.2:c.2945G>A

NM_001130981.2:c.2945G>A

NM_001130982.2:c.2990G>A

NM_001130983.2:c.2897G>A

NM_001130984.2:c.2855G>A

NM_001130985.2:c.2948G>A

NM_001130986.2:c.2855G>A

NM_003494.4:c.2894G>A

Pathogenic

PM2_Supporting PP4_Strong PVS1 PM3

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.2894G>A p.(Trp965Ter) variant in DYSF, which is also known as NM_001130987.2: c.2948G>A p.(Trp983Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 27/55, 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 patients with features consistent with LGMD (PMID: 18853459, 36983702), including confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.757C>T p.(Arg253Trp), 1.0 pt, PMID: 36983702; PM3). At least one individual with this variant and a second DYSF variant displayed progressive proximal muscle weakness and severely reduced dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 18853459, 36983702; PP4_Strong). This variant is 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 1.0.0; 07/29/2025): PVS1, PM3, PP4_Strong, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PP4_Strong

At least one individual with this variant and a second DYSF variant displayed progressive proximal muscle weakness and severely reduced dysferlin protein expression in skeletal muscle or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 18853459, 36983702; PP4_Strong).

PVS1

PM3

This variant has been reported in at least two patients with features consistent with LGMD (PMID: 18853459, 36983702), including confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.757C>T p.(Arg253Trp), 1.0 pt, PMID: 36983702; PM3). c.757C>T p.(Arg253Trp) is at least LP independent of this case

Curation History

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