ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.755-1G>A

gnomAD frequency: 0.00001  dbSNP: rs778614872
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001302186 SCV001491384 uncertain significance Lethal congenital glycogen storage disease of heart 2022-03-19 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. ClinVar contains an entry for this variant (Variation ID: 1005333). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is present in population databases (rs778614872, gnomAD 0.009%). This sequence change affects an acceptor splice site in intron 5 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 RCV004036230 SCV005026325 uncertain significance Cardiovascular phenotype 2024-02-01 criteria provided, single submitter clinical testing The c.755-1G>A intronic variant results from a G to A substitution one nucleotide before coding exon 6 of the PRKAG2 gene. This nucleotide position is well 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. Based on the available evidence, the clinical significance of this alteration remains unclear.

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