ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.264C>G (p.Phe88Leu)

dbSNP: rs144439703
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431950 SCV000520841 likely pathogenic not provided 2023-11-06 criteria provided, single submitter clinical testing Reported as an unclassified variant in a patient who did not have a second variant in POLG and in multiple patients with second variants found to have ataxia and other features (PMID: 25118206, 29474836, 32600829); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32347949, 24508722, 32600829, 21880868, 29474836, 25118206, 32382377)
Labcorp Genetics (formerly Invitae), Labcorp RCV000693072 SCV000820926 uncertain significance Progressive sclerosing poliodystrophy 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 88 of the POLG protein (p.Phe88Leu). This variant is present in population databases (rs144439703, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 21880868, 25118206, 29474836, 32600829). ClinVar contains an entry for this variant (Variation ID: 381522). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. 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.
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.
Baylor Genetics RCV000693072 SCV004205862 pathogenic Progressive sclerosing poliodystrophy 2024-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701468 SCV005204940 likely pathogenic POLG-Related Spectrum Disorders 2024-06-26 criteria provided, single submitter clinical testing Variant summary: POLG c.264C>G (p.Phe88Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 248876 control chromosomes. c.264C>G has been reported in the literature in compound heterozygous or homozygous individuals affected with POLG-Related Spectrum Disorders (Shinagawa_2020, Masingue_2019, Parada-Garza_2020, Tang_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29474836, 32600829, 32382377, 21880868, 25118206). ClinVar contains an entry for this variant (Variation ID: 381522). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000431950 SCV000802097 uncertain significance not provided 2017-11-01 no assertion criteria provided clinical testing

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