ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3640C>T (p.Gln1214Ter) (rs781256643)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579250 SCV000680672 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing The Q1214X variant in the POLG gene has been reported previously in the heterozygous state in an individual with dementia, muscle weakness, easy fatigability, ophthalmoparesis, myopathy, mitochondrial changes, abnormal muscle histology, and abnormal electromyogram/nerve conduction velocity (Tang et al., 2011). This variant is predicted to cause loss of normal protein function through protein truncation. The Q1214X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret Q1214X as a variant of uncertain significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758431 SCV000887135 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3640C>T (NP_002684.1:p.Gln1214Ter) [GRCH38: NC_000015.10:g.89317379G>A] 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.
Invitae RCV000758431 SCV001506455 uncertain significance Progressive sclerosing poliodystrophy 2020-06-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the POLG gene (p.Gln1214*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the POLG protein. This variant is present in population databases (rs781256643, ExAC 0.001%). This variant has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 488798). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

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