ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1433+1G>A (rs771623994)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000359026 SCV000329728 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The c.1433+1 G>A pathogenic variant in the POLG gene has been reported previously in an individual with Alpers syndrome and cardiomyopathy who was compound heterozygous for the c.1433+1 G>A variant and another pathogenic variant (Tang et al., 2011). The c.1433+1 G>A splice site variant destroys the canonical splice donor site in intron 7. 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.1433+1 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1433+1 G>A as a pathogenic variant.
Invitae RCV000758422 SCV000950372 pathogenic Progressive sclerosing poliodystrophy 2018-12-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the POLG 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 (rs771623994, ExAC 0.03%). This variant has been observed in an individual with Alpers syndrome (PMID: 21880868), in whom the variant is in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 280017). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POLG are known to be pathogenic (PMID: 18546365). For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758422 SCV000887126 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1433+1G>A (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89327166C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predicted null variant in POLG where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PM4:This variant causes alteration in the length of expressed protein. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

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