Submissions for variant NM_001130987.2(DYSF):c.3172C>T (p.Arg1058Trp)

dbSNP: rs1553556116

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591140	SCV000704226	likely pathogenic	not provided	2016-12-10	criteria provided, single submitter	clinical testing
Invitae	RCV001376861	SCV001574047	pathogenic	Qualitative or quantitative defects of dysferlin	2023-12-14	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 1040 of the DYSF protein (p.Arg1040Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 23406536, 27066573, 30919934). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498954). 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.
Revvity Omics, Revvity	RCV000591140	SCV002024437	likely pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271535	SCV002555776	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-06-01	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.3118C>T (p.Arg1040Trp) 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 was absent in 250590 control chromosomes. c.3118C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Walter_2013, Izumi_2015, Harris_2016, ten Dam_2019, Morales_2021). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338676	SCV004047870	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B		criteria provided, single submitter	clinical testing	The identified missense variant (c.3172C>T; p.Arg1058Trp) in DYSF gene has been previously reported as (p.Arg1040Trp) in the ClinVar databse. The variant has been previously reported in individuals affected with dysferlinopathy (Izumi R, 2020) and has been reported as Likely Pathogenic by the ClinVar database. In at least one individual affected with dysferlinopathy, the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine with tryptophan at 1058 codon of the DYSF protein. There is a moderate physicochemical difference between arginine and tryptophan. The amino acid change p.Arg1058Trp in DYSF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted to be damaging by both SIFT and PolyPhen2. The p.Arg1058Trp variant is novel (not in any individuals) in gnomAD database. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003465340	SCV004196499	pathogenic	Miyoshi muscular dystrophy 1	2023-07-05	criteria provided, single submitter	clinical testing