Submissions for variant NM_001130987.2(DYSF):c.1276+5G>C

dbSNP: rs766433603

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000311902	SCV000333026	uncertain significance	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV001059832	SCV001224480	likely pathogenic	Qualitative or quantitative defects of dysferlin	2021-07-02	criteria provided, single submitter	clinical testing	Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with DYSF variant in an individual affected with limb-girdle muscular dystrophy (PMID: 29797799). ClinVar contains an entry for this variant (Variation ID: 281954). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 12 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein, but it affects a nucleotide within the consensus splice site of the intron. This variant disrupts the c.1180+5 nucleotide in the DYSF gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18853459, 27290639, 25574751). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469095	SCV002766224	uncertain significance	not specified	2022-11-30	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.1180+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Multiple computational tools predict a significant impact on normal splicing: One predict the variant abolishes a canonical 5' splicing donor site, and another predicts the variant weakens this site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248972 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1180+5G>C has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Feng_2018, Zhong_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.