ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.685-1G>A

gnomAD frequency: 0.00001  dbSNP: rs1824685527
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
AiLife Diagnostics, AiLife Diagnostics RCV002224313 SCV002502532 uncertain significance not provided 2021-10-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003101266 SCV003035216 uncertain significance Lethal congenital glycogen storage disease of heart 2022-02-12 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the PRKAG2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PRKAG2 cause disease.
Ambry Genetics RCV003348818 SCV004073806 uncertain significance Cardiovascular phenotype 2023-07-14 criteria provided, single submitter clinical testing The c.685-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 5 of the PRKAG2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of PRKAG2 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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