ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.139-1del (rs868484837)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000484000 SCV000339908 pathogenic not provided 2017-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000484000 SCV000570206 likely pathogenic not provided 2016-05-20 criteria provided, single submitter clinical testing The c.139-1delG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The c.139-1delG splice site variant destroys the canonical splice acceptor site for intron 3. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of RNA/functional studies, the actual affect of this sequence change is unknown. Although this splice site variant has not been previously reported, other canonical splice site variants have been reported in the Human Gene Mutation Database in association with ANO5-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded
Invitae RCV000793905 SCV000933284 likely pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-12-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the ANO5 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ANO5-related conditions. ClinVar contains an entry for this variant (Variation ID: 286467). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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