Submissions for variant NM_002693.3(POLG):c.2026G>A (p.Ala676Thr)

gnomAD frequency: 0.00001  dbSNP: rs752293938

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000731955	SCV000242177	uncertain significance	not provided	2020-05-13	criteria provided, single submitter	clinical testing	Reported previously in a heterozygous state in an individual with complex I deficiency; however, this patient was also found to have a homozygous pathogenic variant in the ND6 gene that the authors deemed to be the cause of the patient's phenotype (Calvo et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20818383)
Eurofins Ntd Llc (ga)	RCV000731955	SCV000859828	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810598	SCV000950816	uncertain significance	Progressive sclerosing poliodystrophy	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 676 of the POLG protein (p.Ala676Thr). This variant is present in population databases (rs752293938, gnomAD 0.002%). This missense change has been observed in individual(s) with complex I deficiency (PMID: 20818383). ClinVar contains an entry for this variant (Variation ID: 206506). 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 not expected to disrupt POLG 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586612	SCV005076678	uncertain significance	not specified	2024-04-11	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2026G>A (p.Ala676Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251166 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2026G>A has been reported in the literature in a heterozygous individual affected with complex I deficiency who also was homozygous with a pathogenic ND6 variant (Calvo_2010). This report does not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 206506). Based on the evidence outlined above, the variant was classified as uncertain significance.