Submissions for variant NM_007215.4(POLG2):c.496C>G (p.Gln166Glu)

gnomAD frequency: 0.00010  dbSNP: rs370683331

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000314651	SCV000405428	likely benign	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001775769	SCV002012893	uncertain significance	not provided	2019-12-13	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001775769	SCV002208098	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 166 of the POLG2 protein (p.Gln166Glu). This variant is present in population databases (rs370683331, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POLG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 324560). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV004021710	SCV005007112	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	The c.496C>G (p.Q166E) alteration is located in exon 1 (coding exon 1) of the POLG2 gene. This alteration results from a C to G substitution at nucleotide position 496, causing the glutamine (Q) at amino acid position 166 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.