ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.493-2A>C

dbSNP: rs1576857818
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001229857 SCV001402317 likely pathogenic Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2019-09-21 criteria provided, single submitter clinical testing 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CASR are known to be pathogenic (PMID: 22422767). 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. This variant has not been reported in the literature in individuals with CASR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 of the CASR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Neuberg Centre For Genomic Medicine, NCGM RCV003339542 SCV004047837 likely pathogenic Neonatal severe primary hyperparathyroidism criteria provided, single submitter clinical testing The splice site variant c.493-2A>C in CASR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Likely Pathogenic. The c.493-2A>C variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant affects an invariant splice nucleotide and is expected to cause loss of function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic .

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