ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1789C>T (p.Arg597Trp) (rs139717885)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000438492 SCV000704432 pathogenic not provided 2016-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000438492 SCV000520839 likely pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing A published R597W variant that is likely pathogenic has been identified in the POLG gene. The R597W variant has been reported multiple times previously, in both the compound heterozygous and homozygous state, in association with POLG-related disorders (Stewart et al., 2009; Saneto et al., 2010; Tang et al., 2011). The R597W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R597W 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. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758261 SCV000886905 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1789C>T (NP_002684.1:p.Arg597Trp) [GRCH38: NC_000015.10:g.89325610G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS4:Prevalence of variant in affecteds statistically increased over controls. 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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