ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000176550 SCV000255768 pathogenic Limb-girdle muscular dystrophy, type 2B 2014-03-24 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000080255 SCV000613194 pathogenic not provided 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
Counsyl RCV000176550 SCV000789482 pathogenic Limb-girdle muscular dystrophy, type 2B 2017-02-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080255 SCV000337922 pathogenic not provided 2016-06-09 criteria provided, single submitter clinical testing
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
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.
Genetic Services Laboratory, University of Chicago RCV000176550 SCV000247241 pathogenic Limb-girdle muscular dystrophy, type 2B 2014-10-02 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.

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