Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000579081 | SCV000680749 | pathogenic | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | Non-canonical splice site variant demonstrated to result in loss of function (Kergourlay et al., 2014); Observed in a patient with gradual onset of stiffness in the trunk and upper legs (Klinge et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22213072, 19528035, 18396043, 25312915) |
| Revvity Omics, |
RCV000579081 | SCV002024440 | likely pathogenic | not provided | 2019-11-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330808 | SCV004037987 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2023-08-18 | criteria provided, single submitter | clinical testing | Variant summary: DYSF c.1053+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: Four predict the variant abolishes a 5 canonical splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping Exon 11 using a mini-gene system in HEK293T cells (Kergourlay_2014). The variant was absent in 251424 control chromosomes. c.1053+5G>A has been reported in the literature at a compound heterozygous state along with apparently pathogenic variants in at-least two individuals affected with autosomal recessive Miyoshi Myopathy and Distal Anterior Compartment Myopathy (examples, Klinge_2008 and 2010) or Miyoshi muscular dystrophy (Blandin_2012 via UMD-DYSF database), respectively. These data indicate that the variant is likely associated with DYSF-associated diseases including Autosomal Recessive Limb-Girdle Muscular Dystrophy. The following publications have been ascertained in the context of this evaluation (PMID: 22213072, 25312915, 19528035, 18396043). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=1; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |