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

dbSNP: rs2092213253

Total submissions: 4

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 .