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

dbSNP: rs746315830

Total submissions: 7

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.
Eurofins Ntd Llc (ga)	RCV000254734	SCV000335025	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814129	SCV001755393	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV001855002	SCV002224098	pathogenic	Qualitative or quantitative defects of dysferlin	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln111*) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 21522182, 31066050). This variant is also known as c.334C>T, p.Gln112Ter. ClinVar contains an entry for this variant (Variation ID: 265108). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001089583	SCV004192247	pathogenic	Miyoshi muscular dystrophy 1	2023-03-04	criteria provided, single submitter	clinical testing
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