ClinVar Genomic variation as it relates to human health

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.

Variant summary: DYSF c.3041A>G (p.Tyr1014Cys) results in a non-conservative amino acid change located in the Peroxin/Ferlin domain (IPR006614) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250118 control chromosomes (gnomAD). c.3041A>G has been reported in the literature in multiple individuals who carried the variant in compound heterozygous and homozygous state, and were affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Rosales_2010, Harris_2016, and Chakravorty_2020), and the dysferlin protein was found to be absent in the muscle biopsy samples from several of these homozygous patients (Rosales_2010 and Chakravorty_2020). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The identified homozygous missense substitution (p.Tyr1014Cys) lies in exon 29 of the DYSF gene and alters a highly conserved residue in the protein. It lies in the DysF domain of the protein, which has a unique fold, variations in which have been reported to be disease-causing . The variant is predicted to be damaging by FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT. The identified variant has been reported in the dbSNP database with identification number rs756328339 and in the Genome Aggregation Database with an allele frequency of 0.002%; however, no homozygosity has been reported. In the ClinVar database, the identified variant has been reported as pathogenic/likely pathogenic with respect to LGMD. The identified variant has been previously reported in patients affected with dysferlinopathy . The identified missense variant alters a highly conserved residue and is predicted to be damaging to the protein function. It has been previously reported in patients affected with dysferlinopathy. In summary, the variant meets our criteria to be classified as likely pathogenic.

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1014 of the DYSF protein (p.Tyr1014Cys). This variant is present in population databases (rs756328339, gnomAD 0.002%). This missense change has been observed in individual(s) with DYSF-related disease (PMID: 15827562, 20544924). This variant is also known as c.3414A>G. ClinVar contains an entry for this variant (Variation ID: 196175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.