Submissions for variant NM_002693.3(POLG):c.2564T>C (p.Val855Ala)

dbSNP: rs963553787

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758453	SCV000887163	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2564T>C (NP_002684.1:p.Val855Ala) [GRCH38: NC_000015.10:g.89321770A>G] 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758453	SCV002261657	uncertain significance	Progressive sclerosing poliodystrophy	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 855 of the POLG protein (p.Val855Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 18546365, 23830586, 35641312). This variant has been reported in individual(s) with autosomal dominant POLG-related conditions (PMID: 18546365); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 619420). 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.Val855 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 21880868), which suggests that this may be a clinically significant amino acid residue. 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.
GeneDx	RCV003225118	SCV003921546	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	Identified in a child with muscle weakness and progressive external ophthalmoplegia in published literature (Wong et al., 2008); Observed with another POLG variant in a patient with adult-onset bilateral progressive ptosis, progressive external ophthalmoplegia, axonal sensory polyneuropathy, and sensory ataxia (Degos et al., 2014); 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: 18546365, 23830586)