ClinVar Miner

Submissions for variant NM_001927.4(DES):c.735+3A>G (rs267607483)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154574 SCV000204247 pathogenic Primary dilated cardiomyopathy; Myofibrillar myopathy 1 2014-10-10 criteria provided, single submitter clinical testing The 735+3A>G variant in DES has been reported in 6 individuals with desmin myopa thy or limb-girdle muscular dystrophy with 1 de novo occurrence and was found t o segregate with disease in 9 affected individuals from 2 families (Park 2000, D alakas 2000, Wahni 2012, Greenberg 2012 , McDonald 2012, Gudkova 2013, LMM unpub lished data). This variant was absent from large population studies. The 735+3A> G variant is located in the 5' splice region. In vitro splicing studies indicate that this variant may result in the skipping of exon 3, resulting in an in-fram e deletion of 32 amino acids (Park 2000). Additional functional studies indicate this variant leads to abnormal aggregation of desmin fibers (Dalakas 2000, Park 2000). However, these types of assays may not accurately represent biological f unction. In summary, this variant meets our criteria to be classified as pathoge nic for desminopathy in an autosomal dominant manner ( rsonalizedmedicine/LMM) based upon de novo occurrence, segregation studies, abse nce from controls, and functional evidence.
GeneDx RCV000056810 SCV000617236 pathogenic not provided 2017-10-19 criteria provided, single submitter clinical testing The c.735+3 A>G pathogenic variant in DES has been reported previously in the literature in association with desmin-related myopathy, cardiomyopathy, and limb-girdle muscular dytrophy (Dalakas et al., 2000; McDonald et al., 2012; Pugh et al., 2014; Walsh et al., 2017). Dalakas et al. (2000) identified this variant in a 50-year-old female with cardiomyopathy and muscle weakness and found it to be absent in her unaffected parents. In addition, McDonald et al. (2012) reported this variant to segregate with disease in a family who underwent whole exome sequencing for suspected limb-girdle muscular dystrophy. Five of the individuals in this family who harbored the c.735+3 A>G variant had cardiac involvement. Subsequently, Pugh et al. (2014) reported this variant in a 49-year-old female with a diagnosis of DCM with AV block, ventricular tachycardia and a family history of DCM and muscular dystrophy. In silico splice prediction programs predict this variant destroys or reduces the efficiency of the splice donor site in intron 3 and mRNA studies demonstrated that this variant results in the deletion of exon 3 (Dalakas et al., 2000). Other splice site variants, including one impacting the same splice donor site (c.735+1 G>A), have been reported in the DES gene in association with DES-related disorders (Stenson et al., 2014). Furthermore, the c.735+3 A>G variant is not observed in large population cohorts (Lek et al., 2016).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000056810 SCV000706322 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing
Invitae RCV001233592 SCV001406194 pathogenic Myofibrillar myopathy 1; Muscular dystrophy, limb-girdle, type 2R 2020-10-03 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the DES gene. It does not directly change the encoded amino acid sequence of the DES protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with DES-related conditions (PMID: 10717012, 23155419, 24503780, 27532257). In at least one individual the variant was observed to be de novo. This variant is also known in the literature as IVS3+3A>G. ClinVar contains an entry for this variant (Variation ID: 66419). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000056810 SCV000087923 not provided not provided no assertion provided not provided

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