Submissions for variant NM_002693.3(POLG):c.2146C>T (p.Pro716Ser)

gnomAD frequency: 0.00003  dbSNP: rs796052883

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727298	SCV000242183	uncertain significance	not provided	2014-04-15	criteria provided, single submitter	clinical testing	p.Pro716Ser (CCC>TCC): c.2146 C>T in exon 12 of the POLG gene (NM_002693.2). A variant of unknown significance has been identified in the POLG gene. The P716S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 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 P716S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. A missense mutations in a nearby residue (R722H) has been reported in association with myoclonic epilepsy of infancy, supporting the functional importance of this region of the protein. However, in silico analysis predicts the P716S variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in POLG can be inherited in an autosomal recessive or an autosomal dominant manner, although POLG-related disorders causing epilepsy typically have an autosomal recessive inheritance pattern (Cohen et al., 2010). The variant is found in CHILD-EPI panel(s).
Eurofins Ntd Llc (ga)	RCV000727298	SCV000707385	uncertain significance	not provided	2018-03-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727298	SCV002063444	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517006	SCV003243395	uncertain significance	Progressive sclerosing poliodystrophy	2024-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 716 of the POLG protein (p.Pro716Ser). This variant is present in population databases (rs796052883, gnomAD 0.008%). 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: 206512). 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 not expected to disrupt POLG protein function with a negative predictive value of 95%. 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.