ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.334C>T (p.Gln112Ter) (rs746315830)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254734 SCV000321573 pathogenic not provided 2015-11-04 criteria provided, single submitter clinical testing The Q111X pathogenic variant in the DYSF gene has been reported previously in association with various dysferlinopathies in several patients who were either homozygous for the Q111X variant or compound heterozygous for the Q111X variant and another variant in the DYSF gene (Cacciottolo et al., 2011). Individuals homozygous for the Q111X variant showed an absence of dysferlin in their skeletal muscle (Cacciottolo et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q111X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q111X as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000254734 SCV000335025 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV001004980 SCV001164523 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2018-12-03 criteria provided, single submitter research The homozygous p.Gln112Ter variant in DYSF was identified by our study in two unrelated individuals with limb-girdle muscular dystrophy (LGMD). This variant was absent from large popoulation studies. Functional assays of dysferlien protein levels in muscle biopsies from 3 individuals with the variant in the homozygous or heterozygous state and LGMD provide some evidence that the p.Gln112Ter variant may impact protein function (PMID: 21522182). This nonsense variant leads to a premature termination codon at position 112, which is predicted to lead to a truncated or absent protein. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DYSF gene is an established disease mechanism in autosomal recessive LGMD, and this is a loss of function variant. This variant has also been reported pathogenic in ClinVar (Variation ID: 265108). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant. ACMG/AMP Criteria applied: PM2, PVS1, PS3_Supporting (Richards 2015).
Department of Neurology, Guangzhou First People’s Hospital,School of Medicine, South China University of Technology RCV001089583 SCV001244902 pathogenic Miyoshi muscular dystrophy 1 2019-07-01 no assertion criteria provided reference population

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