Submissions for variant NM_002693.3(POLG):c.2890C>T (p.Arg964Cys)

gnomAD frequency: 0.00033  dbSNP: rs201477273

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188591	SCV000242214	uncertain significance	not provided	2024-11-13	criteria provided, single submitter	clinical testing	Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional studies demonstrate that R964C polymerase gamma showed reduced activity in vitro compared to wild-type (PMID: 17436221, 27987238); 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: 19364868, 20176107, 25852747, 20206271, 25462018, 19762913, 27987238, 29992832, 30941926, 31180159, 31521625, 31665838, 32165824, 32005694, 33763395, 33300680, 35314707, 35598585, 34426522, 24091540, 21880868, 17436221, 37470284, 37453004, 18546365)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490261	SCV000267455	likely pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b	2016-03-18	criteria provided, single submitter	reference population
Eurofins Ntd Llc (ga)	RCV000188591	SCV000344604	uncertain significance	not provided	2017-10-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633558	SCV000754804	benign	Progressive sclerosing poliodystrophy	2025-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317145	SCV000849456	uncertain significance	Inborn genetic diseases	2024-10-01	criteria provided, single submitter	clinical testing	The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2890. The arginine at codon 964 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two individuals who were compound heterozygotes for POLG alterations and had a clinical diagnosis of an autosomal recessive POLG-related disorder. One individual was an 8-year-old male diagnosed with mtDNA depletion syndrome, mitochondrial recessive ataxia syndrome, and progressive external ophthalmoplegia (PEO) (Ohba C et al. Neurogenetics. 2013 Nov;14(3-4):225-32). The other individual was a 17-year-old male diagnosed with ataxia neuropathy spectrum (ANS), in addition to cerebellar atrophy, and spinocerebellar ataxia with epilepsy (SCAE) (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). The alteration is location in the polymerase domain and functional studies indicated that there was a decrease in the polymerase activity compared to wild type (Yamanaka H et al. J. Infect. Dis., 2007 May;195:1419-25; Bailey CM et al. Antimicrob. Agents Chemother., 2009 Jun;53:2610-2). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 available evidence, the clinical significance of this variant remains unclear for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant POLG-related progressive external ophthalmoplegia.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000633558	SCV000887118	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000188591	SCV001149560	likely pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000490261	SCV001163769	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000188591	SCV001474646	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. (PMID: 17436221, 19364868, 19887119, 20176107, 25462018, 27987238, 25852747, 37470284) This variant segregates with disease in multiple families.
3billion, Medical Genetics	RCV001808469	SCV002058398	pathogenic	Mitochondrial DNA depletion syndrome 4b	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21880868, 19762913, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17436221, 19364868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 4B (MNGIE type) (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847830	SCV002105577	pathogenic	Hereditary spastic paraplegia	2017-12-01	criteria provided, single submitter	clinical testing
Mendelics	RCV002247604	SCV002519195	pathogenic	not specified	2023-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002247604	SCV002571903	uncertain significance	not specified	2024-10-28	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, 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 0.00068 in 251154 control chromosomes, predominantly at a frequency of 0.0088 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders phenotype. c.2890C>T has been reported in the literature in several individuals affected with clinical features of POLG-Related Spectrum Disorders without strong evidence for causality (example, Yamanaka_2007, Wong_2008, Strickler_2009, Tang_2011, Ohba_2013, Han_2019, Hu_2020, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 14% of normal polymerase gamma enzyme activity in vitro (example, Yamanaka_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19364868, 31665838, 32348839, 34690748, 24091540, 19762913, 21880868, 18546365, 17436221). ClinVar contains an entry for this variant (Variation ID: 206537). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Pediatric Department, Xiangya Hospital, Central South University	RCV003232987	SCV002761223	likely pathogenic	MELAS syndrome		criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with variant (c.2584G>A)
Revvity Omics, Revvity	RCV000188591	SCV003809215	uncertain significance	not provided	2022-03-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000633558	SCV004205903	uncertain significance	Progressive sclerosing poliodystrophy	2023-05-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000188591	SCV004227455	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	BS1, PP3, PM3, PS3
Institute of Human Genetics, University of Leipzig Medical Center	RCV003992217	SCV004812121	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2024-03-27	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3_MOD,PP3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796080	SCV005417341	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		criteria provided, single submitter	clinical testing	PM3_VeryStrong+PP4+PS3+BS1
Fulgent Genetics, Fulgent Genetics	RCV004796080	SCV005633381	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	2024-06-14	criteria provided, single submitter	clinical testing
Codex Genetics Limited	RCV000984890	SCV000996001	pathogenic	Spinocerebellar atrophy	2019-02-28	no assertion criteria provided	provider interpretation
PreventionGenetics, part of Exact Sciences	RCV004732762	SCV005350463	uncertain significance	POLG-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations including Parkinson disease (Hsieh et al. 2019. PubMed ID: 30941926; Kasahara et al. 2017. PubMed ID: 27987238). An in vitro study suggested that this variant may decrease nucleoside analog discrimination and impair the polymerase activity (Bailey et al. 2009. PubMed ID: 19364868). However, this variant has an allele frequency of 0.93% in Eastern Asians, including one homozygote in a large public population database, which may be too frequent to be a primary cause of disease. This variant has also been listed with conflicting interpretations from pathogenic to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/206537/). Although we suspect that this variant may be benign, at this time, we cannot rule out the possibility that this variant may function as a hypomorphic allele, and therefore the clinical significance of this variant is currently classified as uncertain.