Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
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, |
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. |
| Victorian Clinical Genetics Services, |
RCV004786619 | SCV005400144 | likely pathogenic | Mitochondrial disease | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial disease (MONDO#0044970), POLG-related. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants are usually inherited in a recessive manner, however progressive external ophthalmoplegia can also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301791). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (7 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DNA_pol_gammaA domain (NCBI). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. An alternative change, p.(Gly888Ser), has been reported as pathogenic in a compound heterozygous individual with Alpers syndrome (ClinVar, PMID: 17923349). Two other alternative changes, p.(Gly888Arg) and p.(Gly888Cys), have been reported as VUS by clinical laboratories in ClinVar. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in three unrelated individuals, all of whom have a second POLG variant and a diagnosis or Alpers syndrome or suspected mitochondrial disorder (PMIDs: 21880868, 22980518, 21167499, ClinVar). It has also been reported as a VUS by a clinical laboratory in ClinVar, however, the variant was present in a heterozygous state with no second POLG variant identified (personal communicaiton). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |