Submissions for variant NM_002693.3(POLG):c.2446C>G (p.Leu816Val)

gnomAD frequency: 0.00002  dbSNP: rs748262645

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420712	SCV000516981	uncertain significance	not provided	2016-09-23	criteria provided, single submitter	clinical testing	The L816V variant in the POLG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L816V variant was not observed in approximately 6500 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 L816V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret L816V as a variant of uncertain significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758308	SCV000886965	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2446C>G (NP_002684.1:p.Leu816Val) [GRCH38: NC_000015.10:g.89321996G>C] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758308	SCV001226854	uncertain significance	Progressive sclerosing poliodystrophy	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 816 of the POLG protein (p.Leu816Val). This variant is present in population databases (rs748262645, gnomAD 0.004%). 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: 379675). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV003985782	SCV004111106	uncertain significance	POLG-related disorder	2022-11-21	criteria provided, single submitter	clinical testing	The POLG c.2446C>G variant is predicted to result in the amino acid substitution p.Leu816Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89865227-G-C). 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	RCV004782378	SCV005394349	uncertain significance	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2446C>G (p.Leu816Val) results in a conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Four 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 251458 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.2446C>G 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: 379675). Based on the evidence outlined above, the variant was classified as uncertain significance.