Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV005253093 | SCV005903551 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2025-03-19 | reviewed by expert panel | curation | The NM_003494.4: c.2706dup p.(Lys903GlnfsTer4) variant in DYSF, which is also known as NM_001130987.2: c.2760dup p.(Lys921GlnfsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 26/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been observed in at least eight individuals with features consistent with LGMD (PMID: 21522182, 22616201; Jain Foundation Dysferlin Registry internal data communication), including in a homozygous state in one patient without familial consanguinity (0.5 pts) and one Iranian individual with known familial consanguinity (0.25 pts) (Jain Foundation Dysferlin Registry internal data communication). In another patient, it was observed in trans with a likely pathogenic or pathogenic DYSF variant (NM_003494.4: c.4024C>T p.(Arg1342Trp), 1.0 pt, PMID: 21522182, 22616201) (PM3). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness as well as absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 22616201, 21522182; 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; 03/19/2025): PVS1, PM3, PP4_Strong, PM2_Supporting. |
Eurofins Ntd Llc |
RCV000727865 | SCV000855341 | pathogenic | not provided | 2017-09-08 | criteria provided, single submitter | clinical testing | |
Kariminejad - |
RCV001814227 | SCV001755403 | pathogenic | Abnormality of the musculature | 2021-07-10 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000727865 | SCV002544047 | pathogenic | not provided | 2022-05-01 | criteria provided, single submitter | clinical testing | DYSF: PVS1, PM2, PM3:Supporting, PP4 |
Labcorp Genetics |
RCV003574806 | SCV004292569 | pathogenic | Qualitative or quantitative defects of dysferlin | 2023-09-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 592961). This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 21522182, 22616201). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys903Glnfs*4) 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). |