ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.2573C>T (p.Thr858Ile)

gnomAD frequency: 0.00001  dbSNP: rs759128787
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758454 SCV000887164 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2573C>T (NP_002684.1:p.Thr858Ile) [GRCH38: NC_000015.10:g.89321761G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. PM2:This variant is absent in key population databases. 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 Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000758454 SCV000941423 uncertain significance Progressive sclerosing poliodystrophy 2022-05-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 858 of the POLG protein (p.Thr858Ile). This variant is present in population databases (rs759128787, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 30831263, 32161153). ClinVar contains an entry for this variant (Variation ID: 619421). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
GeneDx RCV001536256 SCV001752987 uncertain significance not provided 2021-12-02 criteria provided, single submitter clinical testing Reported previously in a patient with progressive external ophthalmoplegia; segregation information unavailable (Rodriguez-Lopez et al., 2020); Reported previously as a maternally inherited variant of uncertain significance in an individual with developmental delay, hypotonia, and failure to thrive with complex IV and V abnormalities noted on muscle biopsy; clinical information on the mother not provided (Nogueira et al., 2019); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32161153, 30831263)
Ambry Genetics RCV002424756 SCV002740311 uncertain significance Inborn genetic diseases 2021-09-07 criteria provided, single submitter clinical testing The c.2573C>T (p.T858I) alteration is located in exon 16 (coding exon 15) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 2573, causing the threonine (T) at amino acid position 858 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004768628 SCV005380951 uncertain significance not specified 2024-08-16 criteria provided, single submitter clinical testing Variant summary: POLG c.2573C>T (p.Thr858Ile) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2573C>T has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related (Nogueira_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30831263). ClinVar contains an entry for this variant (Variation ID: 619421). Based on the evidence outlined above, the variant was classified as uncertain significance.

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