Submissions for variant NM_002693.3(POLG):c.2557C>T (p.Arg853Trp)

gnomAD frequency: 0.00003  dbSNP: rs121918053

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560575	SCV000630132	likely pathogenic	Progressive sclerosing poliodystrophy	2024-12-10	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 853 of the POLG protein (p.Arg853Trp). This variant is present in population databases (rs121918053, gnomAD 0.003%). This missense change has been observed in individual(s) with early-onset Parkinson disease and/or progressive external ophthalmoplegia and ptosis (PMID: 16401742, 16634032, 27185166). ClinVar contains an entry for this variant (Variation ID: 13512). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.Arg853 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18546365, 19478085, 20185557). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449754	SCV001653029	uncertain significance	not specified	2020-06-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg853Trp variant in POLG has been reported in the compound heterozygous state in an individual affected with progressive external ophthalmoplegia and ptosis 2, and in 2 individuals with early-onset Parkinson's disease and features of mitochondrial disease (segregating with disease in 1 affected family member; Davidzon 2006 PMID: 16634032, Rempe 2016 PMID: 27185166, Gonzalez-Vioque 2006 PMID: 16401742). This variant has also been reported in ClinVar (Variation ID: 13512) and was identified in 4/129112 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Stumpf 2010 PMID: 20185557). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP1, PP3, PM3_Supporting, PS3_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330388	SCV004038495	likely pathogenic	Mitochondrial DNA depletion syndrome	2023-08-09	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2557C>T (p.Arg853Trp) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251374 control chromosomes. c.2557C>T has been reported in the literature as biallelic genotypes in individuals affected with features of autosomal recessive POLG Related-Mitochondrial DNA Depletion Syndrome (example, Davidson_2006, Gonzalez-Vioque_2006, Qualo_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Stumpf_2010). The following publications have been ascertained in the context of this evaluation (PMID: 16634032, 16401742, 33258288, 20185557). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003333951	SCV004041949	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	POLG: PM2, PM3, PM5, PP3, PS3:Supporting
Baylor Genetics	RCV000560575	SCV004205896	pathogenic	Progressive sclerosing poliodystrophy	2024-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005007849	SCV005633394	likely pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2024-04-02	criteria provided, single submitter	clinical testing
OMIM	RCV000014466	SCV000034717	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2006-05-01	no assertion criteria provided	literature only