ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.1898+1G>A (rs142027093)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000479758 SCV000226710 pathogenic not provided 2017-10-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762832 SCV000893191 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L; Miyoshi muscular dystrophy 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000479758 SCV000567319 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing The c.1898+1G>A variant in the ANO5 gene has been reported in the compound heterozygous state inunrelated individuals with Miyoshi distal muscular dystrophy (Linssen et al., 2013), limb girdle musculardystrophy or limb girdle muscle weakness (Witting et al., 2013; Liewluck et al., 2013) and increased CKlevels with dilated cardiomyopathy (Wahbi et al., 2013). The c.1898+1G>A substitution was not observed at asignificant allele frequency in 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. Functionalstudies using mRNA indicate that c.1898+1G>A results in the out-of-frame exclusion of exons 15, 16 and17 (Wahbi et al., 2013). We interpret c.1898+1G>A as a pathogenic variant.
Invitae RCV000627783 SCV000645879 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-11-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 of the ANO5 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 (rs142027093, ExAC 0.02%). This variant has been reported in the compound heterozygous state with a second pathogenic ANO5 variant, c.191dupA (p.Asn64Lysfs*15), in multiple individuals affected with Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy (LGMD) (PMID: 23663589, 23530687, 23670307, 23607914, 23606453). This variant has also been reported in the homozygous state in individuals affected with LGMD (PMID: 23607914), and in the compound heterozygous state with a second ANO5 missense variant in an individual affected with elevated creatine kinase levels and dilated cardiomyopathy (DCM) (PMID: 23041008). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ANO5 are known to be pathogenic (PMID: 21186264, 23606453, 25891276). For these reasons, this variant has been classified as Pathogenic.

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