Submissions for variant NM_002693.3(POLG):c.2419C>T (p.Arg807Cys)

gnomAD frequency: 0.00001  dbSNP: rs769827124

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000261805	SCV000329666	pathogenic	not provided	2022-11-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21880868, 21550804, 16919951, 21357833, 20185557, 28471437, 29655203, 30423451, 33671400, 34179544, 33511646, 30936349, 34052969, 33600046)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547242	SCV000630128	pathogenic	Progressive sclerosing poliodystrophy	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 807 of the POLG protein (p.Arg807Cys). This variant is present in population databases (rs769827124, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive POLG-related disorders (PMID: 16919951, 21357833, 28471437). ClinVar contains an entry for this variant (Variation ID: 279982). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557). This variant disrupts the p.Arg807 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 14635118, 21880868, 28471437), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626194	SCV000746834	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2017-12-18	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000547242	SCV000887115	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2419C>T (NP_002684.1:p.Arg807Cys) [GRCH38: NC_000015.10:g.89322749G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16919951 ; 21550804 . 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. PS3:Well established functional studies show a deleterious effect on POLG. 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. 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.
Institute of Human Genetics, Cologne University	RCV001263147	SCV001441225	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2020-09-30	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000261805	SCV003917422	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	POLG: PM1, PM2, PM3, PM5, PP3, PS3:Supporting
Baylor Genetics	RCV000547242	SCV004205907	pathogenic	Progressive sclerosing poliodystrophy	2023-04-27	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678828	SCV000805014	uncertain significance	neonatal seizures	2017-06-15	flagged submission	clinical testing	present with homozygous ALDH7A1 pathogenic variant
PreventionGenetics, part of Exact Sciences	RCV004732814	SCV005364636	pathogenic	POLG-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The POLG c.2419C>T variant is predicted to result in the amino acid substitution p.Arg807Cys. This variant has been reported in the heterozygous state in multiple individuals with epilepsy or proximal myopathy ptosis diplopia (Table S4, Lindy et al. 2018. PubMed ID: 29655203; Supplemental Table 4, Truty et al. 2019. PubMed ID: 31440721; Ferreira et al. 2011. PubMed ID: 21550804), along with a second POLG variant in multiple individuals with POLG deficiency disorders (see for example, Gago et al. 2006. PubMed ID: 16919951; Ferreira et al. 2011. PubMed ID: 21550804; Keller et al. 2021. PubMed ID: 33600046), and has appeared to segregate with POLG deficiency disorder in at least one family (Supplemental file 1, Hikmat et al. 2017. PubMed ID: 28471437). A functional in vivo study using budding yeast indicates that this variant decreases polymerase activity leading to reduced or depleted mtDNA resulting in mitochondrial disease (Stumpf et al. 2010. PubMed ID: 20185557). Alternate nucleotide changes affecting the same amino acid (p.Arg807Pro, p.Arg807His) have been reported in individuals affected with POLG deficiency disorders (Di Fonzo et al. 2003. PubMed ID: 14635118; Gago et al. 2006. PubMed ID: 16919951; Supplemental file 1, Hikmat et al. 2017. PubMed ID: 28471437). The c.2419C>T variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.