ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1156C>T (p.Arg386Cys) (rs199759055)

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Total submissions: 6
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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 RCV000188650 SCV000609536 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188650 SCV000336723 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing
GeneDx RCV000188650 SCV000242273 likely pathogenic not provided 2018-03-28 criteria provided, single submitter clinical testing The R386C variant in the POLG gene has been reported previously in an individual with isolated distal myopathy of the upper extremities who was compound heterozygous for the R386C variant and another POLG variant (Giordano et al., 2010). In addition, a missense variant at this same codon (R386H) has been reported in association with a POLG-related disorder (Baruffini et al., 2011). The R386C variant is observed in 4/30782 (0.01%) alleles from individuals of South Asian background, in large population cohorts (Lek et al., 2016). The R386C 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 R386C as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778454 SCV000914702 uncertain significance POLG-Related Spectrum Disorders 2018-11-20 criteria provided, single submitter clinical testing The POLG c.1156C>T (p.Arg386Cys) is a missense variant that has been reported in one study and found in one individual with isolated distal myopathy of the upper extremities in the absence of sensory disturbances in a compound heterozygous state with another missense variant (Giordano et al. 2010). This variant was inherited from the unaffected father in a heterozygous state and is reported at a frequency of 0.000182 in the South Asian population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Arg386Cys 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000660573 SCV000782685 uncertain significance Progressive sclerosing poliodystrophy; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-06-19 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758259 SCV000886899 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1156C>T (NP_002684.1:p.Arg386Cys) [GRCH38: NC_000015.10:g.89328699G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:20837862 . This variant meets the following evidence codes reported in the ACMG-guideline. PS3:Well established functional studies show a deleterious effect on POLG. 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 Pathogenic.

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