Submissions for variant NM_002693.3(POLG):c.2584G>A (p.Ala862Thr)

dbSNP: rs778429780

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497335	SCV000589540	likely pathogenic	not provided	2024-03-27	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: 19762913, 19364868, 18546365, 21550804, 22357363, 19251978, 23250882, 22189570, 35598585)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758455	SCV000887165	likely pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2584G>A (NP_002684.1:p.Ala862Thr) [GRCH38: NC_000015.10:g.89321750C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. 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 Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758455	SCV002274369	pathogenic	Progressive sclerosing poliodystrophy	2023-10-03	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 862 of the POLG protein (p.Ala862Thr). This variant is present in population databases (rs778429780, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 18546365, 19762913, 21550804, 22189570, 22357363). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 431952). 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. This variant disrupts the p.Ala862 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Pediatric Department, Xiangya Hospital, Central South University	RCV003232989	SCV002761224	likely pathogenic	MELAS syndrome		criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with variant (c.2890C>T)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330728	SCV004039532	pathogenic	POLG-Related Spectrum Disorders	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2584G>A (p.Ala862Thr) results in a non-conservative amino acid change located in the palm domain (IPR047580) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251356 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2584G>A has been reported in the literature in multiple compound heterozygous individuals affected with POLG-Related Spectrum Disorders (e.g., Wong_2008, Stricker_2009, Ferreira_2011, Lax_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant was unable to complement a null MIP1 (the yeast ortholog of POLG) mutant or restore mitochondrial respiration in yeast (e.g., Stricker_2009). The following publications have been ascertained in the context of this evaluation (PMID: 21550804, 22189570, 19762913, 18546365). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000758455	SCV004205864	pathogenic	Progressive sclerosing poliodystrophy	2023-10-01	criteria provided, single submitter	clinical testing