Submissions for variant NM_002693.3(POLG):c.3287G>A (p.Arg1096His)

gnomAD frequency: 0.00006  dbSNP: rs368435864

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188614	SCV000242237	pathogenic	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Stumpf et al., 2010; Sohl et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 23430834, 23873972, 17280874, 24265579, 23208208, 20185557, 19752458, 23077218, 21880868, 22189570, 20843780, 21305355, 20803511, 23545419, 12707443, 29025585, 22176657, 34288125, 34690748, 25129007, 25340760, 32347949, 16621917, 33046616)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551933	SCV000630143	pathogenic	Progressive sclerosing poliodystrophy	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1096 of the POLG protein (p.Arg1096His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Alpers syndrome or progressive external ophthalmoplegia (PMID: 16621917, 19752458, 35289132). ClinVar contains an entry for this variant (Variation ID: 206557). 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, 23208208). This variant disrupts the p.Arg1096 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707443, 21305355, 21880868, 22189570, 23545419, 24265579). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000188614	SCV000706349	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314742	SCV000848987	likely pathogenic	Inborn genetic diseases	2017-02-10	criteria provided, single submitter	clinical testing	The p.R1096H variant (also known as c.3287G>A), located in coding exon 20 of the POLG gene, results from a G to A substitution at nucleotide position 3287. The arginine at codon 1096 is replaced by histidine, an amino acid with highly similar properties. In one functional study, this alteration's yeast equivalent was found to cause high mytocondrial dysfunction and decreased polymerase activity leading to mtDNA depletion (Stumpf JD et al. Hum. Mol. Genet., 2010 Jun;19:2123-33). In another functional study, this alteration showed decreased affinity for the DNA substrate and decreased rate of nucleotide incorporation, but increased affinity for the incoming nucleotide (Sohl CD et al. Hum. Mol. Genet., 2013 Mar;22:1074-85). In addition, this alteration has been detected in conjunction with POLG p.R627Q in several individuals with phenotypes including: Alpers syndrome, progressive external ophthalmoplegia (PEO), focal nocturnal motor epilepsy with status epilepticus at one month postpartum, and early-onset cerebellar ataxia with PEO; however, phase was not determined in any of these individuals (Horvath R et al. Brain, 2006 Jul;129:1674-84; Schulte C et al. Neurology, 2009 Sep;73:898-900; Savard M et al. Neurology, 2013 Aug;81:770-1; Schicks J et al. Mov. Disord., 2010 Nov;25:2678-82).This amino acid position is highly 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000551933	SCV000887124	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3287G>A (NP_002684.1:p.Arg1096His) [GRCH38: NC_000015.10:g.89318736C>T] 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. 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.
Baylor Genetics	RCV000551933	SCV004205855	likely pathogenic	Progressive sclerosing poliodystrophy	2024-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479051	SCV004222831	pathogenic	POLG-Related Spectrum Disorders	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: POLG c.3287G>A (p.Arg1096His) results in a non-conservative amino acid change located in the palm domain (IPR001098) 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 2e-05 in 251306 control chromosomes (i.e., 5 heterozygotes; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3287G>A has been reported in the literature in multiple compound heterozygous individuals as well as at least one homozygote affected with POLG-Related Spectrum Disorders (e.g., Horvath_2006, Schulte_2009, Savard_2013, Bijarnia-Mahay_2014, Hou_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16621917, 35289132, 19752458, 23873972, 25129007). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004732766	SCV005352065	pathogenic	POLG-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The POLG c.3287G>A variant is predicted to result in the amino acid substitution p.Arg1096His. This variant has been reported in the heterozygous state along with a second POLG variant in individuals with Alpers syndrome, cerebellar ataxia plus sensory neuropathy or external ophthalmoplegia, as well as epilepsy (Table 1, Agostino et al. 2003. PubMed ID: 12707443; Table 1, Horvath et al. 2006. PubMed ID: 16621917; Table 1, Schulte et al. 2009. PubMed ID: 19752458; Savard et al. 2013. PubMed ID: 23873972; Confirmed in the compound heterozygous state, Schicks et al. 2010. PubMed ID: 20803511). Experimental analyses using a yeast-based system suggest this variant leads to a reduction in polymerase activity (Table 1, Stumpf et al. 2010. PubMed ID: 20185557). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Arg1096Cys) has been reported in individuals with POLG-associated disorders and experimental studies suggest it leads to impaired POLG polymerase activity (Mohamed et al. 2011. PubMed ID: 21305355; Table 1, Stumpf et al. 2010. PubMed ID: 20185557; https://preview.ncbi.nlm.nih.gov/clinvar/variation/206556/). The c.3287G>A (p.Arg1096His) variant is interpreted as pathogenic for autosomal recessive POLG1-associated disorders.