Submissions for variant NM_001130987.2(DYSF):c.4078C>T (p.Arg1360Trp)

gnomAD frequency: 0.00010  dbSNP: rs199870606

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000408314	SCV000329869	pathogenic	not provided	2020-01-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21522182, 23488891, 22616201)
Eurofins Ntd Llc (ga)	RCV000408314	SCV000338266	uncertain significance	not provided	2015-12-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802767	SCV000942610	pathogenic	Qualitative or quantitative defects of dysferlin	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1342 of the DYSF protein (p.Arg1342Trp). This variant is present in population databases (rs199870606, gnomAD 0.04%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 21522182). ClinVar contains an entry for this variant (Variation ID: 280068). 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.Arg1342 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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	RCV001804995	SCV002050939	uncertain significance	not specified	2021-12-10	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.4024C>T (p.Arg1342Trp) 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. The variant allele was found at a frequency of 0.00013 in 251288 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00013 vs 0.0031), allowing no conclusion about variant significance. c.4024C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with LGMD2B or dysferlinopathy, who presented with features of a toxic polymyositis (example, Angelini_2011). Dysferlin protein analysis by western blotting showed absent protein in this individual. The variant has also been reported as a heterozygous genotype in affected and unaffected members of a family with with limb-girdle myasthenia in whom the authors identified two other untranslated GFPT1 mutations by exome sequencing (example, Maselli_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2, Pathogenic, n=1). Some submitters cite overlapping evidence utilized in the context of this evalution. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000408314	SCV003830855	likely pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469216	SCV004194225	likely pathogenic	Miyoshi muscular dystrophy 1	2024-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025412	SCV005659315	likely pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2024-06-25	criteria provided, single submitter	clinical testing