Submissions for variant NM_002693.3(POLG):c.3614G>C (p.Gly1205Ala)

dbSNP: rs772737979

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758335	SCV000887000	likely pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3614G>C (NP_002684.1:p.Gly1205Ala) [GRCH38: NC_000015.10:g.89317405C>G] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18546365 . This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758335	SCV000943534	uncertain significance	Progressive sclerosing poliodystrophy	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1205 of the POLG protein (p.Gly1205Ala). This variant is present in population databases (rs772737979, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365). ClinVar contains an entry for this variant (Variation ID: 619343). 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%. This variant disrupts the p.Gly1205 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 23448099), 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	RCV003985818	SCV004749139	uncertain significance	POLG-related disorder	2024-02-08	criteria provided, single submitter	clinical testing	The POLG c.3614G>C variant is predicted to result in the amino acid substitution p.Gly1205Ala. This variant was reported in an individual with developmental delay and seizures (Wong et al. 2008. PubMed ID: 18546365). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Gly1205Glu), has been reported in an individual with POLG-associated disease (Uusimaa et al. 2013. PubMed ID: 23448099). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.