Submissions for variant NM_001130987.2(DYSF):c.6021G>A (p.Trp2007Ter)

gnomAD frequency: 0.00001  dbSNP: rs1553420848

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578874	SCV000681083	pathogenic	not provided	2017-11-16	criteria provided, single submitter	clinical testing	The W1968X variant has been reported in one publication with different cDNA nomenclature (c.6272 G>A) in a patient with limb-girdle muscular dystrophy 2B (De Luna et al., 2007). The W1968X variant is not observed in large population cohorts (Lek et al., 2016). The W1968X nonsense variant in the DYSF gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV001853842	SCV002235605	pathogenic	Qualitative or quantitative defects of dysferlin	2023-07-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 489098). This premature translational stop signal has been observed in individual(s) with DYSF-related conditions (PMID: 16010686, 22194990). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1968*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509453	SCV002819713	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-12-21	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.5904G>A (p.Trp1968X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant was absent in 251446 control chromosomes. p.Trp1968X has been reported in patients with Dysferlinopathy and Limb-Girdle Muscular Dystrophy (Nguyen_2005, De Luna_2007, Gallardo_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.