Submissions for variant NM_001130987.2(DYSF):c.1609G>A (p.Gly537Arg) (rs121908962)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000342783	SCV000329868	pathogenic	not provided	2016-09-26	criteria provided, single submitter	clinical testing	The c.1555 G>A pathogenic variant in the DYSF gene has been previously reported in the homozygous state in two siblings with Miyoshi myopathy and absent dysferlin expression on Western blot. Additionally, it was observed in the heterozygous state in their father with calf myalgias and progressive difficulty with walking (Illa et al., 2007). Functional studies demonstrate the c.1555 G>A variant creates a new splice acceptor site resulting in an out-of-frame deletion of 35 base pairs in exon 18 (De Luna et al., 2007; Kergourlay et al., 2014). This 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000342783	SCV000332008	uncertain significance	not provided	2015-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV001048974	SCV001213004	likely pathogenic	Qualitative or quantitative defects of dysferlin	2019-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 519 of the DYSF protein (p.Gly519Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another DYSF variant in individuals affected with distal myopathy (PMID: 17287450, 30107846). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6679). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 25312915). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM	RCV000007066	SCV000027262	pathogenic	Miyoshi muscular dystrophy 1	2007-04-17	no assertion criteria provided	literature only
Department of Neurology, Guangzhou First People’s Hospital,School of Medicine, South China University of Technology	RCV000342783	SCV001244909	pathogenic	not provided	2019-07-01	no assertion criteria provided	reference population