ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.719C>T (p.Ser240Leu)

gnomAD frequency: 0.00008  dbSNP: rs369175235
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000710189 SCV000242263 uncertain significance not provided 2024-10-11 criteria provided, single submitter clinical testing Identified in an 11 year-old patient with encephalopathy, seizures, posterior stroke and stroke-like episodes, migraines, muscle weakness, and hepatic failure; however, a second POLG variant was not identified and results of parental testing were not provided (PMID: 21880868); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21880868)
Athena Diagnostics RCV000710189 SCV000614734 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001216051 SCV001387823 uncertain significance Progressive sclerosing poliodystrophy 2025-02-02 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 240 of the POLG protein (p.Ser240Leu). This variant is present in population databases (rs369175235, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of POLG-related disease who lacked a second variant in POLG (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 206582). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLG protein function with a negative 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.
Fulgent Genetics, Fulgent Genetics RCV002485276 SCV002790106 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b 2021-11-17 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004732769 SCV005349371 uncertain significance POLG-related disorder 2024-08-09 no assertion criteria provided clinical testing The POLG c.719C>T variant is predicted to result in the amino acid substitution p.Ser240Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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