ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.862C>T (p.Arg288Cys) (rs564582352)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188646 SCV000242269 uncertain significance not provided 2018-01-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The R288C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R288C variant is observed in 22/30614 (0.07%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). The R288C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768290 SCV000898902 uncertain significance Progressive sclerosing poliodystrophy; Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Cerebellar ataxia infantile with progressive external ophthalmoplegia; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-24 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 4 p.Arg288Cys (c.862C>T): This variant has not been reported in the literature and is present in 0.06% (21/30450) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-89872335-G-A). This variant is present in ClinVar (Variation ID:206586). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae RCV000806434 SCV000946433 uncertain significance Progressive sclerosing poliodystrophy 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 288 of the POLG protein (p.Arg288Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs564582352, ExAC 0.09%). This variant has not been reported in the literature in individuals with POLG-related disease. ClinVar contains an entry for this variant (Variation ID: 206586). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188646 SCV001149574 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing

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