ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.264C>G (p.Phe88Leu) (rs144439703)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431950 SCV000520841 likely pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the POLG gene. The F88L variant has been reported previously in trans with a known pathogenic POLG variant in an adult referred for POLG testing but in whom no clinical information was provided (Tang et al., 2011). This variant was subsequently reported as an unclassified variant in a patient who did not have a second variant in POLG and in two patients with second variants found to have ataxia and other features (Tchikviladzé et al., 2015; Masingue et al., 2018). The F88L variant is observed in 7/34380 (0.02%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the F88L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000693072 SCV000820926 uncertain significance Progressive sclerosing poliodystrophy 2018-05-12 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 88 of the POLG protein (p.Phe88Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs144439703, ExAC 0.02%). This variant has been observed in individuals affected with POLG-related disease (PMID: 25118206) and has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with reduced mtDNA copy number in blood but with unknown clinical indication (PMID: 21880868, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 381522). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000431950 SCV000802097 uncertain significance not provided 2017-11-01 no assertion criteria provided clinical testing
Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicine RCV000693072 SCV000887296 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.264C>G (NP_002684.1:p.Phe88Leu) [GRCH38: NC_000015.10:g.89333491G>C] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.

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