Submissions for variant NM_001130987.2(DYSF):c.1717C>T (p.Arg573Trp)

gnomAD frequency: 0.00001  dbSNP: rs377735262

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080241	SCV000331151	pathogenic	not provided	2017-03-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000391157	SCV000431730	pathogenic	DYSF-Related Disorders	2016-06-14	criteria provided, single submitter	clinical testing	The c.1663C>T (p.Arg555Trp) variant has been reported in at least six studies in a total of 10 patients with DYSF-related disorders, including three in a homozygous state and seven in a compound heterozygous state. The p.Arg555Trp variant was absent from 90 controls but is reported at a frequency of 0.00004 in the Total population of the Exome Aggregation Consortium. Functional studies using a myoblast cell line derived from a patient carrying the p.Arg555Trp variant and a second DYSF variant showed that the variant protein was degraded by proteasomes. Treatment with protease inhibitors rescued dysferlin expression and function. Based on the evidence, the p.Arg555Trp variant is classified as pathogenic for DYSF-related disorders.
Athena Diagnostics Inc	RCV000080241	SCV000613184	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
CeGaT Center for Human Genetics Tuebingen	RCV000080241	SCV001247515	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001384924	SCV001584615	pathogenic	Qualitative or quantitative defects of dysferlin	2024-01-01	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 555 of the DYSF protein (p.Arg555Trp). This variant is present in population databases (rs377735262, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 17698709, 25591676, 27066573). ClinVar contains an entry for this variant (Variation ID: 94278). 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 80%. Experimental studies have shown that this missense change affects DYSF function (PMID: 22174839). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000080241	SCV002021890	pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460749	SCV004196527	pathogenic	Miyoshi muscular dystrophy 1	2023-05-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000984167	SCV001132179	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-07-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984167	SCV002079824	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-07-27	no assertion criteria provided	clinical testing