ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.487C>T (p.Pro163Ser)

gnomAD frequency: 0.00004  dbSNP: rs758454871
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000712810 SCV000843343 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000808609 SCV000948723 uncertain significance Progressive sclerosing poliodystrophy 2023-09-17 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 586365). This missense change has been observed in individual(s) with chronic progressiveexternal ophthalmoplegia, seizure, neuropathy, and ataxia (PMID: 22647225). This variant is present in population databases (rs758454871, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the POLG protein (p.Pro163Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323697 SCV004029443 uncertain significance not specified 2023-07-27 criteria provided, single submitter clinical testing Variant summary: POLG c.487C>T (p.Pro163Ser) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) 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 2.9e-05 in 171530 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.487C>T has been reported in the literature in an individual affected with POLG Related condition (example: Woodbridge_2013). These data do not allow any conclusion about variant significance. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Kasahara_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27987238, 22647225). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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