Submissions for variant NM_001130987.2(DYSF):c.1372G>A (p.Gly458Arg)

dbSNP: rs886042093

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000379326	SCV000331206	pathogenic	not provided	2016-01-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244501	SCV001417727	pathogenic	Qualitative or quantitative defects of dysferlin	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the DYSF protein (p.Gly426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related myopathy (PMID: 18853459, 19309282, 32400077, 32528171). This variant is also known as NM_001130987.1:c.1372G>A p.G458R. ClinVar contains an entry for this variant (Variation ID: 281067). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYSF protein function with a positive predictive value of 95%. This variant disrupts the p.Gly426 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15477515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800370	SCV005423635	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-10-01	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.1276G>A (p.Gly426Arg) results in a non-conservative amino acid change located in the Ferlin, third C2 domain (IPR037722) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250996 control chromosomes. c.1276G>A has been reported in the literature in homozygous or compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Bevilacqua_2009, Izumi_2020, Cerino_2022). 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: 19309282, 35741838, 33927379, 32400077, 18853459, 32528171, 25900324). ClinVar contains an entry for this variant (Variation ID: 281067). Based on the evidence outlined above, the variant was classified as likely pathogenic.