ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.460G>A (p.Ala154Thr)

gnomAD frequency: 0.00009  dbSNP: rs753858440
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188635 SCV000242258 uncertain significance not provided 2023-10-27 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign in association with a primary mitochondrial disorder to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26415585, 24150215)
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000661980 SCV000784311 uncertain significance Mitochondrial DNA depletion syndrome 1 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000661981 SCV000784312 uncertain significance Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 2018-03-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000692834 SCV000820677 uncertain significance Progressive sclerosing poliodystrophy 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 154 of the POLG protein (p.Ala154Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206578). 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.
Ambry Genetics RCV002317147 SCV000851585 uncertain significance Inborn genetic diseases 2018-05-14 criteria provided, single submitter clinical testing The p.A154T variant (also known as c.460G>A), located in coding exon 1 of the POLG gene, results from a G to A substitution at nucleotide position 460. The alanine at codon 154 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000692834 SCV000887194 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.460G>A (NP_002684.1:p.Ala154Thr) [GRCH38: NC_000015.10:g.89333295C>T] 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. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Athena Diagnostics RCV000188635 SCV001145167 uncertain significance not provided 2019-07-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000188635 SCV005411144 uncertain significance not provided 2024-01-16 criteria provided, single submitter clinical testing

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