Submissions for variant NM_002693.3(POLG):c.1789C>T (p.Arg597Trp)

dbSNP: rs139717885

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438492	SCV000520839	pathogenic	not provided	2024-04-19	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: 19251978, 25356970, 27538604, 21880868, 20138553, 3346985, 35289132, 33486010, 32650990, 34927673, 34040194, 37184518)
Eurofins Ntd Llc (ga)	RCV000438492	SCV000704432	pathogenic	not provided	2016-12-07	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758261	SCV000886905	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1789C>T (NP_002684.1:p.Arg597Trp) [GRCH38: NC_000015.10:g.89325610G>A] 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. PS4:Prevalence of variant in affecteds statistically increased over controls. 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. 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	RCV000758261	SCV001385759	pathogenic	Progressive sclerosing poliodystrophy	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 597 of the POLG protein (p.Arg597Trp). This variant is present in population databases (rs139717885, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of POLG-related disorders (PMID: 19251978, 20138553, 21880868, 27538604). 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: 381520). 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%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000438492	SCV002019465	pathogenic	not provided	2021-06-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147454	SCV003836267	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2022-02-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000758261	SCV004205893	pathogenic	Progressive sclerosing poliodystrophy	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022346	SCV005007098	pathogenic	Inborn genetic diseases	2023-11-20	criteria provided, single submitter	clinical testing	The c.1789C>T (p.R597W) alteration is located in exon 10 (coding exon 9) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 1789, causing the arginine (R) at amino acid position 597 to be replaced by a tryptophan (W). for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant POLG-related progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.003% (7/250782) total alleles studied. The highest observed frequency was 0.012% (2/16252) of African alleles. This variant has been identified either homozygous or with a second variant in POLG in multiple individuals with clinical features of POLG-related mitochondrial disorders (Saneto, 2010; Béreau, 2016; Bychkov, 2021; Squires, 2023). Another alteration at the same codon, c.1790G>A (p.R597Q), has been reported (Hou, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.