ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1235C>T (p.Pro412Leu)

gnomAD frequency: 0.00003  dbSNP: rs587780420
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118009 SCV000152327 uncertain significance not provided 2013-10-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000804892 SCV000944830 uncertain significance Progressive sclerosing poliodystrophy 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 412 of the POLG protein (p.Pro412Leu). This variant is present in population databases (rs587780420, gnomAD 0.02%). This missense change has been observed in individual(s) with late onset spastic–ataxic gait and multiple lipomas (PMID: 28130605). ClinVar contains an entry for this variant (Variation ID: 129988). 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 disruptive. Experimental studies have shown that this missense change affects POLG function (PMID: 27987238). 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.
Institute of Human Genetics, University of Goettingen RCV000804892 SCV001482439 uncertain significance Progressive sclerosing poliodystrophy 2021-03-03 criteria provided, single submitter clinical testing This variant was found heterozygously in a patient with chronic fatigue syndrome. The variant is absent from gnomAD and not described before. The variant is predicted to be damaging. In summary and based on ACMG criteria PM2, PP3 we classify this variant as Variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen RCV000118009 SCV004033412 uncertain significance not provided 2023-08-01 criteria provided, single submitter clinical testing POLG: PS4:Moderate, PP3
PreventionGenetics, part of Exact Sciences RCV003985726 SCV004114062 uncertain significance POLG-related disorder 2024-03-26 no assertion criteria provided clinical testing The POLG c.1235C>T variant is predicted to result in the amino acid substitution p.Pro412Leu. This variant was reported in an individual with spastic ataxic gait and multiple lipomas (Da Pozzo et al. 2017. PubMed ID: 28130605) and an individual with bipolar disorder (Kasahara et al. 2017. PubMed ID: 27987238). In vitro functional study showed that exonuclease activity of this variant was lower compared to control, while polymerase activity remained unchanged (Kasahara et al. 2017. PubMed ID: 27987238). This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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