Submissions for variant NM_001130987.2(DYSF):c.1615T>C (p.Cys539Arg)

dbSNP: rs1573929182

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004943	SCV001164467	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Cys539Arg variant in DYSF was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD increases the likelihood that the p.Cys539Arg variant is pathogenic. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Cys539Arg variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3 (Richards 2015).
Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital	RCV001004943	SCV005061565	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2025-02-03	criteria provided, single submitter	clinical testing	This variant was detected in a patient with progressive upper and lower limb weakness since 40s and elevated creatine kinase. A muscle biopsy has confirmed dysferlinopathy. This variant is confirmed to be in trans to another known pathogenic variant in DYSF. This variant is found in extremely low frequency with a single heterozygote on gnomAD v4.1.0. In silico analysis suggests the variant to be damaging (REVEL 0.89). There is one report on ClinVar where this variant was also detected in compound heterozygous state with another pathogenic variant in a patient with LGMD phenotype.