ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3285C>G (p.Ser1095Arg) (rs761649878)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441353 SCV000520836 likely pathogenic not provided 2017-08-28 criteria provided, single submitter clinical testing The S1095R variant in the POLG gene has been reported previously in the compound heterozygous state, opposite of a second POLG pathogenic variant, in several unrelated children who presented with myocerebrohepatopathy spectrum (Horst et al., 2014; Tang et al., 2011; Blok et al., 2009). Additionally, the S1095R variant was reported in the heterozygous state in an adult with with ptosis, hearing loss, muscle weakness and optic atrophy (Wong et al., 2008). The S1095R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S1095R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The S1095R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
GenomeConnect, ClinGen RCV000709798 SCV000840123 not provided POLG-Related disorder no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758419 SCV000887122 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3285C>G (NP_002684.1:p.Ser1095Arg) [GRCH38: NC_000015.10:g.89318738G>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:19578034 . 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. 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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