ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.388C>T (p.Leu130Phe)

gnomAD frequency: 0.00003  dbSNP: rs201261842
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000706965 SCV000836041 uncertain significance Progressive sclerosing poliodystrophy 2023-11-09 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 130 of the POLG protein (p.Leu130Phe). This variant is present in population databases (rs201261842, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 582802). 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.
Athena Diagnostics RCV000712807 SCV000843340 uncertain significance not provided 2018-06-13 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003985808 SCV004722077 uncertain significance POLG-related disorder 2024-01-18 criteria provided, single submitter clinical testing The POLG c.388C>T variant is predicted to result in the amino acid substitution p.Leu130Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0032% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89876598-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004702363 SCV005204318 uncertain significance not specified 2024-06-13 criteria provided, single submitter clinical testing Variant summary: POLG c.388C>T (p.Leu130Phe) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 186602 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.388C>T in individuals affected with POLG-Related Spectrum Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 582802). Based on the evidence outlined above, the variant was classified as uncertain significance.

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