Submissions for variant NM_002693.3(POLG):c.1721G>A (p.Arg574Gln)

gnomAD frequency: 0.00001  dbSNP: rs764287987

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758294	SCV000886948	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1721G>A (NP_002684.1:p.Arg574Gln) [GRCH38: NC_000015.10:g.89325678C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM2:This variant is absent in key population databases. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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 Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791102	SCV000930375	likely pathogenic	POLG-related disorder	2019-04-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758294	SCV001560774	likely pathogenic	Progressive sclerosing poliodystrophy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 574 of the POLG protein (p.Arg574Gln). This variant is present in population databases (rs764287987, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of autosomal recessive POLG-related conditions (PMID: 28815208, 33258288). ClinVar contains an entry for this variant (Variation ID: 619321). 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.Arg574 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16621917, 16896309, 19125351, 20601675, 20883824, 27987238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001585689	SCV001819612	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26640698, 34927673, 32943091, 33258288, 28815208)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117542	SCV003800915	uncertain significance	not specified	2024-01-25	criteria provided, single submitter	clinical testing	Variant summary: POLG c.1721G>A (p.Arg574Gln) results in a conservative amino acid change located in the spacer domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 245180 control chromosomes (gnomAD). c.1721G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with features of POLG-Related Spectrum Disorders (example, Ng_2017 initially cited in Bargiela_2015, Quaio_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26640698, 28815208, 33258288). ClinVar contains an entry for this variant (Variation ID: 619321). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000758294	SCV004205860	likely pathogenic	Progressive sclerosing poliodystrophy	2024-03-14	criteria provided, single submitter	clinical testing