ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3139C>T (p.Arg1047Trp) (rs181860632)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188603 SCV000242226 likely pathogenic not provided 2017-10-09 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the POLG gene. The R1047W variant has been previously reported in several unrelated patients who all had a second detectable POLG mutation, consistent with autosomal recessive inheritance of POLG-related disorders causing juvenile-onset Alpers syndrome, progressive external ophthalmoplegia (PEO) with ataxia, and peripheral neuronopathy with mtDNA deletions (Wiltshire et al., 2008; Stewart et al., 2009; Lax et al., 2012). The R1047W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1047W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in the sane residue (R1047Q) and nearby residues (V1044A, G1051R) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188603 SCV000281261 pathogenic not provided 2015-08-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188603 SCV000705543 uncertain significance not provided 2017-09-20 criteria provided, single submitter clinical testing
Invitae RCV000633548 SCV000754794 uncertain significance Progressive sclerosing poliodystrophy 2020-09-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1047 of the POLG protein (p.Arg1047Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs181860632, ExAC 0.02%). This variant has been reported in the literature as biallelic with other missense POLG variants in several individuals affected with Alper's syndrome and chronic progressive external ophthalmoplegia (PMID: 18195149, 22189570. 19251978), and as heterozygous in an individual with complex I deficiency (PMID: 20818383). ClinVar contains an entry for this variant (Variation ID: 206548). This variant is located within a polymerase domain of POLG that is important for keeping the balance between pol and exo activity of this mitochondrial replicase. A structure-function molecular model developed specifically for the POLG gene suggests that this missense change may result in diminishing the fidelity of the polymerase intrinsic process and thus has been determinated to be deleterious (PMID: 21824913). However, this prediction has not been confirmed by published functional studies and its 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000188603 SCV000802079 likely pathogenic not provided 2020-06-08 criteria provided, single submitter clinical testing PS4_moderate, PM2, PM3, PM5, PP5
Ambry Genetics RCV000720665 SCV000851544 uncertain significance Seizures 2018-11-24 criteria provided, single submitter clinical testing The p.R1047W variant (also known as c.3139C>T), located in coding exon 19 of the POLG gene, results from a C to T substitution at nucleotide position 3139. The arginine at codon 1047 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was first reported in conjunction with a missense alteration (phase not specified) in an individual with suspected juvenile Alpers disease (occipital seizures, peripheral neuropathy, migraines, neuronal loss and gliosis predominantly in occipital lobe, mitochondrial DNA deletions in liver) and was absent among over 200 control alleles (Wiltshire E et al. Arch. Neurol., 2008 Jan;65:121-4). In another study, this variant was reported in conjunction with a missense alteration (phase not specified) in an individual with progressive external ophthalmoplegia (PEO), ataxia, and two affected siblings with spinocerebellar ataxia (SCA)-like phenotype (Stewart JD et al. J. Med. Genet., 2009 Mar;46:209-14; Lax NZ et al. Brain, 2012 Jan;135:62-71). 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 variant remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000633548 SCV000887120 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18195149 . This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.

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