Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000696449 | SCV000825012 | pathogenic | Qualitative or quantitative defects of dysferlin | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 286 of the DYSF protein (p.Val286Glu). This variant is present in population databases (rs398123807, gnomAD 0.0009%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 18832576, 25493284, 32528171, 33610434, 33927379). ClinVar contains an entry for this variant (Variation ID: 94365). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV000080333 | SCV003833273 | likely pathogenic | not provided | 2023-01-13 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330426 | SCV004039342 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2023-08-03 | criteria provided, single submitter | clinical testing | Variant summary: DYSF c.857T>A (p.Val286Glu) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Althought the variant alters the second nucleotide of exon 9 near the 3' splice acceptor junction, computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes. c.857T>A has been reported in the literature in compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive 2B or dysferlinopathy (e.g. Dominov_2014, Harris_2016, Charnay_2021, Kesari_2021, Moore_2021) or in an individual with undiagnosed limb-girdle weakness with unspecified variant zygosity (e.g. Topf_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24488599, 33927379, 25493284, 27602406, 18832576, 33610434, 32528171). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Eurofins Ntd Llc |
RCV000080333 | SCV000112228 | uncertain significance | not provided | 2012-09-04 | flagged submission | clinical testing | |
| Natera, |
RCV001831823 | SCV002079774 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2B | 2021-01-12 | flagged submission | clinical testing |