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.5646G>A (p.Trp1882Ter)

CA10606170

288647 (ClinVar)

Gene: DYSF (HGNC:8291)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: 5b97ae9d-2b14-4d4d-ae43-d5183c297c99

Approved on: 2025-01-08

Published on: 2025-01-08

HGVS expressions

NM_001130987.2(DYSF):c.5646G>A (p.Trp1882Ter)

NM_001130987.2:c.5646G>A

NC_000002.12:g.71669608G>A

CM000664.2:g.71669608G>A

NC_000002.11:g.71896738G>A

CM000664.1:g.71896738G>A

NC_000002.10:g.71750246G>A

NG_008694.1:g.220986G>A

ENST00000698057.1:c.3060G>A

ENST00000698058.1:c.2277G>A

ENST00000698059.1:c.2385G>A

ENST00000258104.8:c.5529G>A

ENST00000410020.8:c.5646G>A

ENST00000258104.7:c.5529G>A

ENST00000394120.6:c.5532G>A

ENST00000409366.5:c.5595G>A

ENST00000409582.7:c.5643G>A

ENST00000409651.5:c.5625G>A

ENST00000409744.5:c.5553G>A

ENST00000409762.5:c.5580G>A

ENST00000410020.7:c.5646G>A

ENST00000410041.1:c.5583G>A

ENST00000413539.6:c.5622G>A

ENST00000429174.6:c.5592G>A

ENST00000479049.6:n.2414G>A

NM_001130455.1:c.5532G>A

NM_001130976.1:c.5487G>A

NM_001130977.1:c.5550G>A

NM_001130978.1:c.5592G>A

NM_001130979.1:c.5622G>A

NM_001130980.1:c.5580G>A

NM_001130981.1:c.5643G>A

NM_001130982.1:c.5625G>A

NM_001130983.1:c.5595G>A

NM_001130984.1:c.5553G>A

NM_001130985.1:c.5583G>A

NM_001130986.1:c.5490G>A

NM_001130987.1:c.5646G>A

NM_003494.3:c.5529G>A

NM_001130455.2:c.5532G>A

NM_001130976.2:c.5487G>A

NM_001130977.2:c.5550G>A

NM_001130978.2:c.5592G>A

NM_001130979.2:c.5622G>A

NM_001130980.2:c.5580G>A

NM_001130981.2:c.5643G>A

NM_001130982.2:c.5625G>A

NM_001130983.2:c.5595G>A

NM_001130984.2:c.5553G>A

NM_001130985.2:c.5583G>A

NM_001130986.2:c.5490G>A

NM_003494.4:c.5529G>A

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.5529G>A p.(Trp1843Ter) variant in DYSF, which is also known as NM_001130987.2: c.5646G>A p.(Trp1882Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 50/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least two unrelated individuals with dysferlinopathy. One patient was homozygous (0.5 pts, PMID: 17994539) while in the second patient, the variant was identified in unknown phase with a confirmed pathogenic variant (c.2811-2A>C, 1.0 pt, PMID: 30564623) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 17994539). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/08/2025): PVS1, PM3, PP4_Strong, PM2_Supporting.

PM3

This variant has been detected in at least two unrelated individuals with dysferlinopathy. One patient was homozygous (0.5 pts, PMID: 17994539) while in the second patient, the variant was identified in unknown phase with a confirmed pathogenic variant (c.2811-2A>C, 1.0 pt, PMID: 30564623) (PM3).

PVS1

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).

PP4_Strong

At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 17994539).

Curation History

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