Submissions for variant NM_003494.3(DYSF):c.2643+1G>A (rs140108514)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000176550	SCV000247241	pathogenic	Limb-girdle muscular dystrophy, type 2B	2014-10-02	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000176550	SCV000255768	pathogenic	Limb-girdle muscular dystrophy, type 2B	2014-03-24	criteria provided, single submitter	clinical testing
Center for Genetic Medicine Research,Children's National Medical Center	RCV000233433	SCV000265772	likely pathogenic	Miyoshi muscular dystrophy 1	2015-12-01	criteria provided, single submitter	research
GeneDx	RCV000080255	SCV000329662	pathogenic	not provided	2016-07-29	criteria provided, single submitter	clinical testing	The c.2643+1 G>A splice site variant in the DYSF gene has been previously reported in individuals with LGMD2B and Miyoshi mypopathy who harbored a second pathogenic variant on the opposite allele (Takahashi et al., 2013; Krahn et al., 2009). This pathogenic variant destroys the canonical splice donor site in intron 25 and functional studies have demonstrated that it results in skipping of exon 25, leading to abnormal gene splicing (Kergourlay et al., 2014). The c.2643+1 G>A variant was not observed at a significant frequency in approximately 6500 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 c.2643+1 G>A as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000080255	SCV000337922	pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000080255	SCV000613194	pathogenic	not provided	2014-03-24	criteria provided, single submitter	clinical testing
Counsyl	RCV000176550	SCV000789482	pathogenic	Limb-girdle muscular dystrophy, type 2B	2017-02-14	criteria provided, single submitter	clinical testing
Invitae	RCV000697172	SCV000825769	pathogenic	Dysferlinopathy	2019-01-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 25 of the DYSF gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs140108514, ExAC 0.2%). This variant has been reported in many individuals affected with autosomal recessive limb-girdle muscular dystrophy and Miyoshi myopathy (PMID: 12796534, 22246893, 23243261, 18853459, 27854218, 21816046). This variant is also known as c.3016+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 94291). Experimental studies have shown that this splicing change results in skipping of exon 25 (PMID: 25312915). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000763504	SCV000894294	pathogenic	Miyoshi muscular dystrophy 1; Limb-girdle muscular dystrophy, type 2B; Myopathy, distal, with anterior tibial onset	2018-10-31	criteria provided, single submitter	clinical testing
Broad Institute Rare Disease Group,Broad Institute	RCV000176550	SCV001164531	pathogenic	Limb-girdle muscular dystrophy, type 2B	2018-12-03	criteria provided, single submitter	research	The heterozygous c.2697+1G>A variant in DYSF was identified by our study in one individual in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.1706% (41/24026) of African chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140108514). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The c.2697+1G>A variant in DYSF has been reported in 3 individuals with LGMD (PMID: 23243261). The presence of this variant in combination with reported pathogenic variants and in 2 individuals with LGMD increases the likelihood that the c.2697+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.2697+1G>A variant may impact protein function by causing abnormal splicing of Exon 25 (PMID: 25312915). However, these types of assays may not accurately represent biological function.This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an in-frame transcript deletion and abnormal or absent protein. Loss of function In the DYSF gene is an established disease mechanism in autosomal recessive LGMD. In summary, the clinical significance of the 2697+1G>A variant is pathogenic. ACMG/AMP Criteria applied: PVS1_Moderate, PS3, PM3_Strong (Richards 2015).