ClinVar Miner

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

dbSNP: rs886043966
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen RCV004999239 SCV005620312 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-08 reviewed by expert panel curation 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.
Eurofins Ntd Llc (ga) RCV000371436 SCV000342817 pathogenic not provided 2016-06-09 criteria provided, single submitter clinical testing
GeneDx RCV000371436 SCV000890306 pathogenic not provided 2022-09-27 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17994539)
Baylor Genetics RCV003469245 SCV004192248 pathogenic Miyoshi muscular dystrophy 1 2023-02-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003574728 SCV004292579 pathogenic Qualitative or quantitative defects of dysferlin 2024-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1843*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy type 2B (LGMD2B) (PMID: 17994539). ClinVar contains an entry for this variant (Variation ID: 288647). For these reasons, this variant has been classified as Pathogenic.

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