ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000176550 SCV000247241 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2014-10-02 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 The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Invitae RCV000697172 SCV000825769 pathogenic Qualitative or quantitative defects of dysferlin 2019-12-18 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; Autosomal recessive 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 Autosomal recessive 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,; 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).
Myriad Women's Health, Inc. RCV000176550 SCV001193993 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2019-12-24 criteria provided, single submitter clinical testing NM_003494.3(DYSF):c.2643+1G>A is classified as pathogenic in the context of dysferlinopathy. Sources cited for classification include the following: PMID 24488599 and 25312915. Classification of NM_003494.3(DYSF):c.2643+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Natera, Inc. RCV000176550 SCV001458659 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2020-09-16 no assertion criteria provided clinical testing

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