Submissions for variant NM_001130987.2(DYSF):c.5642+1G>A

dbSNP: rs727503915

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000407918	SCV000331558	pathogenic	not provided	2014-01-23	criteria provided, single submitter	clinical testing
Invitae	RCV000648019	SCV000769829	pathogenic	Qualitative or quantitative defects of dysferlin	2022-07-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DYSF protein in which other variant(s) (p.Asp1837Asn) have been determined to be pathogenic (PMID: 11257469, 22194990). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 49, but is expected to preserve the integrity of the reading-frame (PMID: 21522182). ClinVar contains an entry for this variant (Variation ID: 167030). Disruption of this splice site has been observed in individual(s) with DYSF-related conditions (PMID: 21522182). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 49 of the DYSF gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469027	SCV002766227	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-11-08	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.5525+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 228924 control chromosomes. c.5525+1G>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy and Miyoshi myopathy (Cacciottolo_2011, Walter_2013), with one family reported as compound heterozygous, carrying a second (likely) pathogenic variant. These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003467212	SCV004192273	pathogenic	Miyoshi muscular dystrophy 1	2022-12-28	criteria provided, single submitter	clinical testing