Submissions for variant NM_001130987.2(DYSF):c.1449G>A (p.Met483Ile) (rs146064054)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000726239	SCV000343118	uncertain significance	not provided	2018-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000726239	SCV000536482	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing	The c.1353 G>A variant in the DYSF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1353 G>A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. In-silico splice prediction models predict that c.1353 G>A may damage or destroy the splice donor site in exon 14. However, in the absence of RNA/functional studies, the actual effect of c.1353 G>A change in this individual is unknown. If c.1353 G>A does not alter splicing, it will result in the M451I missense change. The M451I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.1353 G>A as a variant of uncertain significance.
Claritas Genomics	RCV000449523	SCV000537828	uncertain significance	Peripheral neuropathy	2016-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV000648013	SCV000769823	uncertain significance	Qualitative or quantitative defects of dysferlin	2019-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with isoleucine at codon 451 of the DYSF protein (p.Met451Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 14 of the DYSF coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs146064054, ExAC 0.06%). This variant has not been reported in the literature in individuals with DYSF-related disease. ClinVar contains an entry for this variant (Variation ID: 288879). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.