ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2419C>T (p.Arg807Cys) (rs769827124)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678828 SCV000805014 uncertain significance neonatal seizures 2017-06-15 criteria provided, single submitter clinical testing present with homozygous ALDH7A1 pathogenic variant
GeneDx RCV000261805 SCV000329666 likely pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing The R807C variant has been reported previously in one individual with epilepsy and encephalopathy, one individual with encephalopathy, liver failure, and lactic acidosis, and one individual with sensory ataxia with neuropathy, dysarthria and ophthalmoparesis (SANDO). All of these individuals carried another POLG variant, although the phase of the variants was not confirmed (Isohanni et al., 2011; Tang et al., 2011; Gago et al., 2006). Functional studies suggest the R807C variant causes decreased polymerase activity leading to mitochondrial DNA depletion and mitochondrial dysfunction (Stumpf et al., 2010). The R807C variant is observed in 5/30782 (0.02%) alleles from individuals of South Asian background, in large population cohorts (Lek et al., 2016). The R807C 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. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000626194 SCV000746834 pathogenic Cerebellar ataxia infantile with progressive external ophthalmoplegia 2017-12-18 criteria provided, single submitter clinical testing
Invitae RCV000547242 SCV000630128 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 807 of the POLG protein (p.Arg807Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs769827124, ExAC 0.02%). This variant has been reported in several individuals affected with individuals affected with POLG-related disorders (PMID: 16919951, 21550804, 21357833). ClinVar contains an entry for this variant (Variation ID: 279982). Experimental studies have shown that this missense change leads to decreased polymerase activity, mtDNA depletion and mitochondrial dysfunction (PMID: 20185557). This variant disrupts the p.Arg807 amino acid residue in POLG. Other variants that disrupt this residue have been observed in affected individuals (PMID: 21880868, 14635118), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000547242 SCV000887115 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2419C>T (NP_002684.1:p.Arg807Cys) [GRCH38: NC_000015.10:g.89322749G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16919951 ; 21550804 . 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. 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. 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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