Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002298436 | SCV005903549 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2025-03-18 | reviewed by expert panel | curation | The NM_003494.4: c.5057+5G>A variant in DYSF, which is also known as NM_001130987.2: c.5174+5G>A, occurs within the splice donor motif of intron 45. RNAseq and cDNA analysis has demonstrated that this variant disrupts splicing, resulting in a frameshift and premature truncation, with no detectable normally spliced transcript (PMID: 36983702, 10766988; PVS1_RNA). This variant has been identified in at least two patients with LGMD, including in a homozygous state (0.25 pts, PMID: 10766988) and in unknown phase with a pathogenic variant (c.5979dup p.(Glu1994ArgfsTer3), 0.5 pts, PMID: 36983702) (PM3_Supporting). At least one patient with this variant displayed progressive limb girdle muscle weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Moderate, PMID: 36983702, 10766988). The variant was shown to co-segregate with the LGMD phenotype in five affected members of a consanguineous family of Yemenite Jewish descent (PP1_Moderate; PMID: 10766988). The highest population minor allele frequency is 0.00002196 (2/91068 exome alleles) in the South Asian population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (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; 03/18/2025): PVS1_RNA, PM3_Supporting, PP4_Moderate, PP1_Moderate, PM2_Supporting. |
| Revvity Omics, |
RCV001781198 | SCV002024431 | likely pathogenic | not provided | 2019-05-10 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001851715 | SCV002247204 | pathogenic | Qualitative or quantitative defects of dysferlin | 2023-09-10 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 45 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs745891180, gnomAD 0.006%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing, which introduces a frameshift and introduces a premature termination codon (PMID: 10766988). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 6672). This variant is also known as a G to A bp alteration that is predicted to affect position 5 in the intron following amino acid 1686. This variant has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 10766988). It has also been observed to segregate with disease in related individuals. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002298436 | SCV002598752 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2022-09-26 | criteria provided, single submitter | clinical testing | Variant summary: DYSF c.5057+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 8e-06 in 251286 control chromosomes. c.5057+5G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV003466824 | SCV004194223 | likely pathogenic | Miyoshi muscular dystrophy 1 | 2023-09-02 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000007057 | SCV000027253 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2B | 2000-04-10 | no assertion criteria provided | literature only |