Submissions for variant NM_002693.3(POLG):c.915C>G (p.Ser305Arg)

gnomAD frequency: 0.00001  dbSNP: rs769410130

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188649	SCV000242272	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced DNA affinity and nucleotide mismatch excision rate, leading to a reduction in mtDNA content and increase in mtDNA mutation frequency (Qian et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22000311, 19578034, 21824913, 18546365, 21880868, 25914719, 20883824, 30860128)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758271	SCV000886923	likely pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.915C>G (NP_002684.1:p.Ser305Arg) [GRCH38: NC_000015.10:g.89329051G>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:19578034 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Likely Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995844	SCV001150221	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2019-06-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000188649	SCV001250419	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758271	SCV001377915	pathogenic	Progressive sclerosing poliodystrophy	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 305 of the POLG protein (p.Ser305Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 19578034, 20883824, 22000311). ClinVar contains an entry for this variant (Variation ID: 206588). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. Experimental studies have shown that this missense change affects POLG function (PMID: 20883824, 25914719, 26095671). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001332170	SCV001524403	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2020-03-26	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID 19578034 etc.]
Ambry Genetics	RCV002372152	SCV002684842	likely pathogenic	Inborn genetic diseases	2020-01-30	criteria provided, single submitter	clinical testing	The p.S305R variant (also known as c.915C>G), located in coding exon 3 of the POLG gene, results from a C to G substitution at nucleotide position 915. The serine at codon 305 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in three individuals with Alpers syndrome who also carried POLG p.A467T (phase was not confirmed) (Hunter MF et al. Pediatr. Neurol., 2011 Nov;45:311-8; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Hakonen AH et al. Eur. J. Hum. Genet., 2007 Jul;15:779-83) as well as in one individual with Alpers syndrome without a second identifiable alteration (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). In addition, this alteration was detected in one individual with generalized seizures, myoclonic jerks, ataxia, and sensory-axonal peripheral neuropathy who also carried POLG p.R627Q and in one individual with muscular hypotonia, status epilepticus, repeated vomiting, severe lactic acidosis, and liver failure who may have also carried POLG p.P1073L (Baruffini E et al. Mitochondrion, 2011 Jan;11:182-90). In two functional studies, authors showed that this alteration significantly reduces DNA binding affinity of the mitochondrial DNA polymerase gamma and results in increased mutability and loss of mitochondrial DNA (Baruffini E et al. Mitochondrion, 2011 Jan;11:182-90; Qian Y et al. Front Genet, 2015 Apr;6:135) This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV000758271	SCV004205881	pathogenic	Progressive sclerosing poliodystrophy	2023-08-29	criteria provided, single submitter	clinical testing