ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.2697+1G>C

dbSNP: rs140108514
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Total submissions: 2
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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 RCV004998721 SCV005620308 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-08 reviewed by expert panel curation The NM_003494.4: c.2643+1G>C variant in DYSF, which is also known as NM_001130987.2: c.2697+1G>C, occurs within the canonical splice donor site of intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids (PVS1_Moderate). This variant has been confirmed in trans with a likely pathogenic variant in an individual with a clinical diagnosis of LGMD (c.4194C>A p.(Cys1398Ter), 1.0 pt, PMID: 21522182) (PM3). This patient also showed absent dysferlin expression, which is highly specific for DYSF-related LGMD (PP4_Strong). The variant was reported to co-segregate with the disease in one affected family member (PP1). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). Another nucleotide change affecting the same splice site and with the same predicted splice effect, NM_003494.4: c.2643+1G>A, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP. 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_Moderate, PM3, PP4_Strong, PP1, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001205457 SCV001376717 pathogenic Qualitative or quantitative defects of dysferlin 2025-01-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 25 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with DYSF-related conditions (PMID: 21522182, 22246893). ClinVar contains an entry for this variant (Variation ID: 936623). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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