ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.3526-2A>G (rs797045031)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191067 SCV000245459 pathogenic Hypokalemic periodic paralysis 1 2014-10-22 criteria provided, single submitter clinical testing This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory maternally inherited in a 22-year-old male with global delays, hypotonia, muscle weakness & wasting, hypertonia, abnormal movements
Invitae RCV001376984 SCV001574200 likely pathogenic Hypokalemic periodic paralysis 1; Malignant hyperthermia, susceptibility to, 5 2020-10-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 27 of the CACNA1S 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 been observed in individual(s) with clinical features of hypokalemic periodic paralysis (PMID: 26633545). ClinVar contains an entry for this variant (Variation ID: 209137). 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 CACNA1S are known to be pathogenic (PMID: 26247046, 28012042). 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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