ClinVar Miner

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

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Total submissions: 5
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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.

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