ClinVar Miner

Submissions for variant NM_213599.2(ANO5):c.41-1G>A (rs398124625)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000176019 SCV000255644 pathogenic Limb-girdle muscular dystrophy, type 2L 2013-11-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082852 SCV000227601 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000082852 SCV000329926 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing The c.41-1G>A pathogenic variant in the ANO5 gene has been reported previously in the compound heterozygous state with another pathogenic variant in an individual with limb-girdle muscular dystrophy (van der Kooi et al., 2013). This splice site variant destroys the canonical splice acceptor site in intron 1. 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. The c.41-1G>A variant was not observed in approximately 6400 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.41-1G>A as a pathogenic variant.
Invitae RCV000645359 SCV000767103 pathogenic Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy, type 2L 2018-05-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 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 (rs398124625, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic and in combination with other ANO5 variants in individuals affected with limb-girdle muscular dystrophy and hyperCKemia and periodic loss of ambulation (PMID: 23607914, Invitae). These finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 96685). 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. 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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