Submissions for variant NM_002693.3(POLG):c.2474T>C (p.Val825Ala)

gnomAD frequency: 0.00001  dbSNP: rs763453929

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188577	SCV000242199	uncertain significance	not provided	2012-07-30	criteria provided, single submitter	clinical testing	p.Val825Ala (GTG>GCG):c.2474 T>C in exon 15 of the POLG gene (NM_002693.2). The Val825Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Val825Ala in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Valine and Alanine are both uncharged, non-polar amino acids. Val825Ala alters a conserved position in the polymerase domain of the protein where many missense mutations have been reported in association with POLG-related disorders. Some in silico algorithms predict it may be damaging to protein structure/function, while another model suggests it may not be pathogenic. Therefore, based on the currently available information, it is unclear whether Val825Ala is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
CeGaT Center for Human Genetics Tuebingen	RCV000188577	SCV004137631	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	POLG: PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765198	SCV004640581	uncertain significance	Progressive sclerosing poliodystrophy	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 825 of the POLG protein (p.Val825Ala). This variant is present in population databases (rs763453929, 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: 206525). 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 80%. 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.