ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.970C>T (p.Pro324Ser) (rs2307437)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000127555 SCV000171132 benign not specified 2013-11-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000710190 SCV000341137 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing
Invitae RCV000468571 SCV000543875 uncertain significance Progressive sclerosing poliodystrophy 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 324 of the POLG protein (p.Pro324Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs2307437, ExAC 0.05%). This variant has been reported in individuals with suspected POLG-deficiency (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 21320). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Athena Diagnostics Inc RCV000710190 SCV000614738 uncertain significance not provided 2018-09-26 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000468571 SCV000887106 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.970C>T (NP_002684.1:p.Pro324Ser) [GRCH38: NC_000015.10:g.89328996G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). 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 Benign.
Illumina Clinical Services Laboratory,Illumina RCV001121509 SCV001280134 uncertain significance POLG-Related Spectrum Disorders 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneReviews RCV000020485 SCV000040922 benign Mitochondrial diseases 2012-10-11 no assertion criteria provided curation Converted during submission to Benign.

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