ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3218C>T (p.Pro1073Leu) (rs267606959)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188673 SCV000242297 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing The P1073L variant in the POLG gene has been identified in patients who harbored another POLG variant on the other allele and were diagnosed with Alpers syndrome or other POLG-related disorders causing epilepsy, intellectual disability, gastrointestinal issues, and liver delay (Tang et al., 2011; Kurt et al., 2010; Baruffini et al., 2011). The P1073L variant is observed in 5/245628 (0.002%) alleles in large population cohorts (Lek et al., 2016). The P1073L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Functional studies indicate that P1073L affects mtDNA replication (Qian et al., 2015). We interpret P1073L as a pathogenic variant.
Undiagnosed Diseases Network,NIH RCV000014470 SCV000837701 pathogenic Progressive sclerosing poliodystrophy 2018-01-03 criteria provided, single submitter clinical testing This variant has been reported in mulitple individuals with this Alpers phenotype (MIM 203700) in the literature. There is also one paper with data from yeast model (PMID:20883824).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000014470 SCV000886987 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3218C>T (NP_002684.1:p.Pro1073Leu) [GRCH38: NC_000015.10:g.89318986G>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. PS3:Well established functional studies show a deleterious effect on POLG. 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. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 RCV000014470 SCV000936270 pathogenic Progressive sclerosing poliodystrophy 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1073 of the POLG protein (p.Pro1073Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs267606959, ExAC 0.02%). This variant has been observed in several individuals affected with autosomal recessive Alpers syndrome segregating with disease in a family (PMID: 20142534, 25914719, 20883824, 21880868). ClinVar contains an entry for this variant (Variation ID: 13516). Experimental studies have shown that this missense change abolishes POLG protein function (PMID: 25914719, 20883824). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014470 SCV000034721 pathogenic Progressive sclerosing poliodystrophy 2010-02-01 no assertion criteria provided literature only
OMIM RCV000014471 SCV000034722 pathogenic Mitochondrial DNA depletion syndrome 4B, MNGIE type 2010-02-01 no assertion criteria provided literature only

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