ClinVar Miner

Submissions for variant NM_021098.3(CACNA1H):c.3744+1G>A

gnomAD frequency: 0.00001  dbSNP: rs770718464
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255511 SCV000321499 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing The c.3744+1G>A variant in the CACNA1H gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 17. 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.3744+1G>A variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret c.3744+1G>A as a variant of uncertain significance, which may be related to the epilepsy reported
Labcorp Genetics (formerly Invitae), Labcorp RCV000555691 SCV000632144 uncertain significance Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV 2018-09-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 of the CACNA1H 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 (rs770718464, ExAC 0.009%) but has not been reported in the literature in individuals with a CACNA1H-related disease. ClinVar contains an entry for this variant (Variation ID: 265069). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547). However, current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA1H cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance.

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