ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.2509T>C (p.Tyr837His)

gnomAD frequency: 0.00004  dbSNP: rs544828395
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000518238 SCV000614714 uncertain significance not specified 2017-05-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001210666 SCV001382163 uncertain significance Progressive sclerosing poliodystrophy 2024-07-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 837 of the POLG protein (p.Tyr837His). This variant is present in population databases (rs544828395, gnomAD 0.03%). This missense change has been observed in individual(s) with POLG-related disorders (PMID: 25488682). ClinVar contains an entry for this variant (Variation ID: 448103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001764514 SCV001989398 uncertain significance not provided 2019-07-11 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Neuberg Centre For Genomic Medicine, NCGM RCV003338630 SCV004048101 uncertain significance Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 criteria provided, single submitter clinical testing The missense variant c.2509T>C (p.Tyr837His) in POLG gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge . This variant has been reported to the ClinVar database as Uncertain Significance. The p.Tyr837His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.003579% is reported in gnomAD. The amino acid Tyr at position 837 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Tyr837His in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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