Submissions for variant NM_002693.3(POLG):c.3155G>A (p.Gly1052Asp)

dbSNP: rs769328030

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757679	SCV000885997	uncertain significance	not provided	2018-01-28	criteria provided, single submitter	clinical testing	The POLG p.Gly1052Asp variant has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. The p.Gly1052Asp variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.00081% (identified in 2 out of 246,020 chromosomes), which indicates that it is not a common polymorphism. The glycine at codon 1052 is highly conserved considering 12 species up to baker’s yeast (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the POLG protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, the available information is not sufficient to determine the clinical significance of the p.Gly1052Asp variant with certainty.
Athena Diagnostics	RCV000757679	SCV001879835	uncertain significance	not provided	2021-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855898	SCV002186953	uncertain significance	Progressive sclerosing poliodystrophy	2024-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1052 of the POLG protein (p.Gly1052Asp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 28865037). ClinVar contains an entry for this variant (Variation ID: 618839). 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 expected to disrupt POLG protein function with a positive predictive value of 95%. This variant disrupts the p.Gly1052 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 28865037), which suggests that this may be a clinically significant amino acid residue. 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	RCV004723154	SCV005338094	uncertain significance	POLG-related disorder	2024-08-30	no assertion criteria provided	clinical testing	The POLG c.3155G>A variant is predicted to result in the amino acid substitution p.Gly1052Asp. This variant was reported in two individuals with Alpers syndrome, along with a second POLG variant for which the phase of the variants was not described (Supplementary Table, Hikmat et al. 2017. PubMed ID: 28865037). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.