ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.2697+5G>A

dbSNP: rs2092213253
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Total submissions: 4
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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 RCV005253904 SCV005903550 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-03-18 reviewed by expert panel curation The NM_003494.4: c.2643+5G>A variant in DYSF, which is also known as NM_001130987.2: c.2697+5G>A, occurs in a splice donor motif in intron 25. It is predicted to cause skipping of biologically relevant exon 25/55, resulting in an in-frame deletion of 44 amino acids. Skipping of exon 25 was confirmed by RNAseq (PMID 36983702; PVS1_Moderate_RNA). This variant has been identified in at least one individual with features consistent with LGMD, where it was reported in unknown phase with a pathogenic variant (NM_003494.4: c.3113G>A p.(Arg1038Gln), 0.5 pts, PMID: 33610434, 36983702; PM3_Supporting). This patient displayed progressive weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702). The highest population minor allele frequency is 0.000001695 (2/11800362 alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Another nucleotide change affecting the same splice site and with the same experimentally demonstrated 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 (PS1). 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_Moderate_RNA, PM3_Supporting, PP4_Strong, PS1, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV002042107 SCV002110659 uncertain significance Qualitative or quantitative defects of dysferlin 2022-02-05 criteria provided, single submitter clinical testing This sequence change falls in intron 25 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 33610434). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.2643+5 nucleotide in the DYSF gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 27647186; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Jain Foundation RCV002042107 SCV003922049 likely pathogenic Qualitative or quantitative defects of dysferlin 2023-03-13 criteria provided, single submitter research This variant is not present in population databases (gnomAD has no frequency). It has also been identified in one family with dysferlinopathy, segregated with the disease in 2 affected relatives, and was associated with absent dysferlin protein expression (PMID: 36983702). This variant was also found in the heterozygous state in conjunction with another pathogenic DYSF variant (NM_003494.4:c.3113G>A). RNASeq analysis showed that the c.2643+5G>A variant results in the complete skipping of exon 25, which leads to an inframe deletion of 44 amino acids (p.Tyr838_Thr881del; PMID: 36983702). The ACMG classification criteria are: PM2 moderate, PM3 supporting, PM4 moderate, PP1 supporting, PP4 moderate. Based on the above data, this variant has been classified as Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV003339763 SCV004047839 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2B criteria provided, single submitter clinical testing The splice site variant c.2697+5G>A in DYSF gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as a variant of Uncertain Significance with no no functional evidence for this variation. The c.2697+5G>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant is close to the canonical splice-site, and the position is strongly conserved. The variant is predicted to affect splicing and loss-offunction is a known mechanism of disease. For these reasons, this variant has been classified as Variant of Uncertain Significance .

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