Submissions for variant NM_002693.3(POLG):c.2663G>A (p.Gly888Asp)

dbSNP: rs878854560

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227514	SCV000287669	uncertain significance	Progressive sclerosing poliodystrophy	2016-03-19	criteria provided, single submitter	clinical testing	In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in combination with a pathogenic variant in an individual affected with a POLG-related disease (PMID: 21880868). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 888 of the POLG protein (p.Gly888Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000227514	SCV000886975	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2663G>A (NP_002684.1:p.Gly888Asp) [GRCH38: NC_000015.10:g.89321196C>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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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 Pathogenic.