ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2897T>G (p.Leu966Arg) (rs142347031)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413284 SCV000490737 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing The L966R pathogenic variant in the POLG gene has been reported in association with autosomal recessive POLG-related disorders, including Alpers syndrome (Nguyen et al., 2006; McCoy et al., 2011; Hunter et al., 2011; Uusimaa et al., 2013). The L966R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The L966R 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. We interpret L966R as a pathogenic variant.
Invitae RCV000821077 SCV000961819 likely pathogenic Progressive sclerosing poliodystrophy 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 966 of the POLG protein (p.Leu966Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs142347031, ExAC 0.005%). This variant has been observed in individuals affected with Alpers syndrome (PMID: 16545482, 22000311, 17426723) or epilepsy (PMID: 23448099, 21704543). This variant is also known as c.3179T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 372473). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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