Submissions for variant NM_002693.3(POLG):c.1493A>C (p.Lys498Thr)

gnomAD frequency: 0.00003  dbSNP: rs769637557

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766611	SCV000242284	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28471437, 28865037)
Athena Diagnostics	RCV000188661	SCV000614703	uncertain significance	not specified	2017-06-12	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758406	SCV000887097	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1493A>C (NP_002684.1:p.Lys498Thr) [GRCH38: NC_000015.10:g.89327004T>G] 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. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). PP3:Computational evidence/predictors indicate the variant has deleterious effect on 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	RCV000758406	SCV001383150	uncertain significance	Progressive sclerosing poliodystrophy	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 498 of the POLG protein (p.Lys498Thr). This variant is present in population databases (rs769637557, gnomAD 0.008%). This missense change has been observed in individual(s) with Alpers syndrome (PMID: 28471437). ClinVar contains an entry for this variant (Variation ID: 206597). 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. 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.
Ambry Genetics	RCV002517885	SCV003548288	uncertain significance	Inborn genetic diseases	2021-07-20	criteria provided, single submitter	clinical testing	Hikmat, 2017a; Hikmat, 2017b Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000188661	SCV005394299	uncertain significance	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: POLG c.1493A>C (p.Lys498Thr) results in a non-conservative amino acid change in 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 4.8e-05 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders, allowing no conclusion about variant significance. c.1493A>C has been reported in the literature in individuals affected with Alpers syndrome or Cerebellar Ataxia (Hikmat_2017, Coutelier_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29482223, 28471437, 28865037, 34690748). ClinVar contains an entry for this variant (Variation ID: 206597). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766611	SCV005411137	uncertain significance	not provided	2023-08-29	criteria provided, single submitter	clinical testing	PP3, PM2_moderate, PM3_supporting
PreventionGenetics, part of Exact Sciences	RCV004732771	SCV005347872	uncertain significance	POLG-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The POLG c.1493A>C variant is predicted to result in the amino acid substitution p.Lys498Thr. This variant was reported with a second POLG variant in an individual with Alpers syndrome (Supp. Table 1 in Hikmat et al 2017. PubMed ID: 28865037). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.