ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1685G>A (p.Arg562Gln)

dbSNP: rs781168350
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV001270233 SCV001364364 likely pathogenic Premature ovarian failure 2020-03-02 criteria provided, single submitter research
Ambry Genetics RCV002411731 SCV002715865 uncertain significance Inborn genetic diseases 2017-06-27 criteria provided, single submitter clinical testing The p.R562Q variant (also known as c.1685G>A), located in coding exon 8 of the POLG gene, results from a G to A substitution at nucleotide position 1685. The arginine at codon 562 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in an individual with progressive external ophthalmoplegia and myopathy, who was negative for ANT1 and C10orf2 mutations; however, no second allele was identified in the POLG gene (Di Fonzo A et al. Hum Mutat. 2003;22:498-9). An in vitro study suggested that this alteration might attenuate enzyme activity (Kasahara T et al. Psychiatry Clin Neurosci. 2016;Dec [Epub ahead of print: doi: 10.1111/pcn.12496]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003985839 SCV004721900 uncertain significance POLG-related disorder 2023-10-18 no assertion criteria provided clinical testing The POLG c.1685G>A variant is predicted to result in the amino acid substitution p.Arg562Gln. This variant has been reported in an individual with progressive external ophthalmoplegia (Di Fonzo et al. 2003. PubMed ID: 14635118), and individual with bipolar disorder (Kasahara et al. 2017. PubMed ID: 27987238), and an individual with primary ovarian insufficiency (Table S3 in Bestetti et al. 2021. PubMed ID: 34480478). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89869870-C-T). Although we suspect that this variant may be pathogenic, 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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