ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.830A>T (p.His277Leu) (rs138929605)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000188643 SCV000281184 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188643 SCV000855031 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000188643 SCV000242266 uncertain significance not provided 2018-06-15 criteria provided, single submitter clinical testing The H277L variant in the POLG gene has been reported previously multiple times in association withPOLG-related disorders in individuals who were also heterozygous for a second missense variant in thePOLG gene, although phase was not determined for most of these patients (Ashley et al., 2008;Hunter et al., 2011; Sato et al., 2011; an external gene database). However,H277L has also been reported in siblings with infantile hepatopathy where pathogenic variants werefound in cis and in trans to H277L (Hunter et al., 2011). The H277L variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size and/or other properties. H277L occurs at a position that is predicted to be withinthe exonuclease domain of the protein where many missense pathogenic variants have been reportedin association with POLG-related disorders (external gene database).However, this substitution occurs at a position that is not conserved. In summary, based on thecurrently available information, it is unclear whether this variant is a pathogenic variant or a rarebenign variant.
Illumina Clinical Services Laboratory,Illumina RCV000396333 SCV000394295 uncertain significance POLG-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing The POLG c.830A>T (p.His277Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two patients (Ashley et al. 2008; Sato et al. 2011). The variant was absent from 50 controls, but is reported at a frequency of 0.00069 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.His277Leu variant had normal DNA binding affinity and was found to have similar exonuclease activity and DNA strand displacement activity in vitro as compared to wild type (Macao et al. 2015). The evidence for this variant is limited. The p.His277Leu variant is classified as a variant of unknown significance, but suspicious for pathogenicity for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000231645 SCV000287676 pathogenic Progressive sclerosing poliodystrophy 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 277 of the POLG protein (p.His277Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is present in population databases (rs138929605, ExAC 0.07%). This variant has been reported as compound heterozygous in individuals affected with Alpers syndrome (PMID: 18487244), progressive sensory ataxic neuropathy with cerebellar features (PMID: 22357363), and progressive external ophthalmoplegia with parkinsonism (PMID: 21301859). In two of these individuals, this variant was shown to segregate with disease (PMID: 22357363, 21301859). It has also been reported as a single variant in individuals with seizures (PMID: 21880868) as well as unaffected individuals (PMID: 22357363). ClinVar contains an entry for this variant (Variation ID:206583) Experimental studies have shown that introducing this variant at the equivalent amino acid in the yeast POLG protein reduces the protein exonuclease activity (PMID: 22114710, 24508722, 27987238). However, it has also been shown that the human protein with this variant behaved similarly to wild-type protein in several in vitro assays (PMID: 26095671). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000616176 SCV000712078 likely pathogenic Mitochondrial DNA depletion syndrome 2016-05-15 criteria provided, single submitter clinical testing The p.His277Leu variant in POLG has been previously reported in one child with A lpers syndrome (Ashley 2008), one patient with progressive external ophthalmople gia and parkinsonism (Sato 2011), one patient with mitochondrial DNA depletion s yndrome presenting as sensory ataxic neuropathy with cerebellar features (McKelv ie 2012). All three patients were compound heterozygotes. This variant has been identified in 48/121174 of chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs138929605). Although this variant has been seen in the general population, its frequency is low enough to be consisten t with a recessive carrier frequency. Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.His277Leu variant is likely pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000231645 SCV000886921 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.830A>T (NP_002684.1:p.His277Leu) [GRCH38: NC_000015.10:g.89330106T>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:18487244 . 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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