Submissions for variant NM_001130987.2(DYSF):c.1225C>T (p.Arg409Ter) (rs758180890)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255632	SCV000322445	likely pathogenic	not provided	2018-05-21	criteria provided, single submitter	clinical testing	The R377X variant in the DYSF gene has been reported previously in the presence of a second nonsense variant in the DYSF gene, in an individual with Miyoshi myopathy, characterized by running, stair-climbing, and standing difficulties, gait disturbances, muscle atrophy, elevated CK, dystrophic changes on muscle biopsy, and decreased/absent dysferlin expression in skeletal muscle (Park et al., 2012). Another individual with a family history of muscular dystrophy, elevated CK levels, mild dystrophic features on muscle biopsy, and normal clinical phenotype at the age of 14 years, reportedly harbored the R377X variant, along with a splice site DYSF variant (Seong et al., 2015). The R377X is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is observed in 4/34,420 (0.0116%) alleles from individuals of Latino background, and in 7/277,136 total alleles in large population cohorts (Lek et al., 2016). We interpret R377X as a likely pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000255632	SCV000701005	pathogenic	not provided	2015-12-08	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000763502	SCV000894292	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Myopathy, distal, with anterior tibial onset	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000817143	SCV000957688	pathogenic	Qualitative or quantitative defects of dysferlin	2019-10-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg377*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs758180890, ExAC 0.02%). This variant has been observed in an individual affected with a DYSF-related condition (PMID: 22297152). ClinVar contains an entry for this variant (Variation ID: 265487). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). For these reasons, this variant has been classified as Pathogenic.
GenomeConnect, ClinGen	RCV000509478	SCV000606978	not provided	DYSF- Related Disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.