Submissions for variant NM_002693.3(POLG):c.1760C>T (p.Pro587Leu)

gnomAD frequency: 0.00160  dbSNP: rs113994096

Total submissions: 50

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193529	SCV000248555	pathogenic	not specified	2019-07-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000427845	SCV000331603	pathogenic	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415307	SCV000492823	pathogenic	Global developmental delay	2014-07-15	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000427845	SCV000511317	pathogenic	not provided	2016-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV000408293	SCV000543885	uncertain significance	Progressive sclerosing poliodystrophy	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (rs113994096, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Thr251Ile) variant (PMID: 12210792, 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. To date, the p.Pro587Leu variant has not been observed independent from the p.Thr251Ile variant in individuals with autosomal recessive POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 13505). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). In summary, this is a rare variant that is almost always observed in cis with a second variant. It has been shown to segregate with disease, and has also been observed in many individuals with sporadic disease. However, because it almost always occurs in cis with p.Thr251Ile, the individual contribution of this variant to disease cannot be disambiguated. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc	RCV000427845	SCV000614707	pathogenic	not provided	2019-04-16	criteria provided, single submitter	clinical testing	This variant is seen in cis with POLG c.752C>T (p.Thr251Ile), and the pathogenicity assessment is based on data for NM_002693.2:c.752C>T(;)1760C>T.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000186576	SCV000680342	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2017-11-08	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000020473	SCV000746435	pathogenic	Mitochondrial DNA depletion syndrome 1	2017-12-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000427845	SCV000802089	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	PP3, PM2, PS3_moderate
Ambry Genetics	RCV002313709	SCV000847670	pathogenic	Inborn genetic diseases	2018-11-30	criteria provided, single submitter	clinical testing	The p.P587L pathogenic mutation (also known as c.1760C>T), located in coding exon 9 of the POLG gene, results from a C to T substitution at nucleotide position 1760. The proline at codon 587 is replaced by leucine, an amino acid with similar properties. This mutation has been reported to occur almost exclusively in cis with p.T251I (c.752C>T) and this syntenic mutation combination accounts for approximately 6% of all disease causing alleles in POLG (Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). This syntenic mutation combination has been detected alone, in trans with various other POLG mutations and alterations, and as homozygous, in individuals with Alpers syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability and various other POLG-deficiency symptoms (Van Goethem G et al. Eur. J. Hum. Genet., 2003 Jul;11:547-9; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Uusimaa J et al. Epilepsia, 2013 Jun;54:1002-11; Weiss MD et al. Muscle Nerve, 2010 Jun;41:882-5; Horvath R et al. Brain, 2006 Jul;129:1674-84; Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). Of note, this mutation has been detected without p.T251I in conjunction with the p.R853W alteration (phase was not confirmed) in an individual with PEO, ptosis, and multiple mtDNA deletions (González-Vioque E et al. Arch. Neurol., 2006 Jan;63:107-11). In addition, biochemical characterization of P587L mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than P587L alone (DeBalsi KL et al. J. Biol. Chem., 2017 03;292:4198-4209). Based on the supporting evidence, p.P587L is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000427845	SCV000884404	likely pathogenic	not provided	2018-04-06	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000408293	SCV000886904	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 ; 12825077 . 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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.
Mendelics	RCV000408293	SCV001139681	uncertain significance	Progressive sclerosing poliodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000427845	SCV001149568	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM2:Supporting, PS3:Supporting
Baylor Genetics	RCV001004602	SCV001163772	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000427845	SCV001446808	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000408293	SCV001448887	likely pathogenic	Progressive sclerosing poliodystrophy	2019-01-10	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001642226	SCV001519175	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2021-01-04	criteria provided, single submitter	research
Baylor Genetics	RCV000408293	SCV001529893	pathogenic	Progressive sclerosing poliodystrophy	2018-06-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. These two variants have been previously reported as pathogenic and are frequently in cis configuration [PMID 12210792, 19189930, 23665194, 28154168, 22616202, 25585994, 23783014, 26468652, 19566497, 20513108, 24122062]
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813986	SCV001755620	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000408293	SCV001760353	likely pathogenic	Progressive sclerosing poliodystrophy		criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001610290	SCV001832553	pathogenic	Tip-toe gait	2021-02-10	criteria provided, single submitter	clinical testing	c.1760C>T p.(Pro587Leu) [dbSNP: rs113994096, Frequenz: A=0.15%, GnomAD] is rated by the majority (15 entries) as "probably pathogenic" and "pathogenic" in the ClinVar mutation database.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000014456	SCV001950111	uncertain significance	Mitochondrial DNA depletion syndrome 4b	2021-07-27	criteria provided, single submitter	clinical testing	Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000427845	SCV002011121	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
DASA	RCV001813743	SCV002061213	pathogenic	POLG-related disorder	2022-01-05	criteria provided, single submitter	clinical testing	The c.1760C>T;p.(Pro587Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13505; OMIM 174763.0011; PMID: 12825077; 25660390; 12975295; 1539879; 19578034; 24265579; 23448099;25742477; 26224072) - PS4.The p.(Pro587Leu) was detected in trans with a pathogenic variant (PMID: 19578034) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 25660390) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847603	SCV002105557	likely pathogenic	Hereditary spastic paraplegia	2021-11-22	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000427845	SCV002503521	likely pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002227034	SCV002506434	uncertain significance	Stroke disorder	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,BP1
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001004602	SCV002512294	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b	2022-02-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong, PP3 supporting
Genetics and Molecular Pathology, SA Pathology	RCV000014456	SCV002556643	likely pathogenic	Mitochondrial DNA depletion syndrome 4b	2023-04-05	criteria provided, single submitter	clinical testing	The POLG c.1760C>T variant is classified as LIKELY PATHOGENIC (PS3, PS4_moderate, PP1_moderate, PP3) This sequence change in exon 10 of 23 replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (gnomAD 232/152196 heterozygotes, 0 homozygote). The variant has been reported in dbSNP (rs113994096). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 13505). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it has been observed on the same chromosome (in cis) with the second (p.Thr251Ile) variant also detected in this patient (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868) (PS4_moderate). In many of these previously reported cases, the two variants in cis were observed on the opposite chromosome (in trans) from a third, pathogenic variant in an affected individual. The p.Pro587Leu and p.Thr251Ile variant combination in cis accounts for approximately 6% of disease-causing alleles in POLG-related disorders, mainly in Caucasians (PMID: 21880868). The p.Pro587Leu and Thr251Ile variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879) (PP1_moderate). Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168) (PS3). NO THIRD POLG variant was detected in this patient
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001813743	SCV002568173	pathogenic	POLG-related disorder	2022-06-02	criteria provided, single submitter	clinical testing	PS3, PM3_Strong, PP1, PP3
3billion	RCV000186576	SCV002572626	likely pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.154%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013505). The variant was observed in cis with NM_002693.3:c.752C>T (p.Thr251Ile) in many individuals affected with POLG-related diseases (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000186576	SCV002581640	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-07-29	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000186576	SCV002587017	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2021-07-27	criteria provided, single submitter	research
Genetic Medico-Diagnostic Laboratory Genica	RCV002319424	SCV002605540	pathogenic	Hypertrophic cardiomyopathy	2022-10-19	criteria provided, single submitter	clinical testing	The variant was classified as pathogenic according to the ACMG Guidelines, 2015. The variant was found with an allele frequency of 0.1540% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. In silico analysis by Polyphen-2, SIFT and Mutation-Taster predicted it as damaging. The amino acid change is in a highly conserved position and proline and leucine have moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.752C>T in a patient with Hypertrophic cardiomyopathy. The patient is also carrier of variants GTPBP3(NM_032620.4):c.181G>C and GTPBP3(NM_032620.4):c.1199C>T in compound heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001813743	SCV003804668	likely pathogenic	POLG-related disorder	2022-12-19	criteria provided, single submitter	clinical testing	_x000D_Criteria applied: PS3, PS4_SUP, PP3, PP1
Revvity Omics, Revvity	RCV000427845	SCV003818479	pathogenic	not provided	2023-07-11	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000014456	SCV003843876	likely pathogenic	Mitochondrial DNA depletion syndrome 4b	2021-02-13	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 10 of the POLG gene that results in the amino acid substitution of Leucine for Proline at codon587 was detected. The observed variant c.1760C>T (p.Pro587Leu) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV001813743	SCV004801567	pathogenic	POLG-related disorder	2021-06-17	criteria provided, single submitter	clinical testing	The POLG c.1760C>T p.(Pro587Leu) missense variant is well described in the literature and has been reported in individuals with a phenotype consistent with POLG-related spectrum disorders (Van Goethem et al., 2003; Filosto et al. 2003; Lamantea et al. 2004; Wong et al., 2008; Ashley et al., 2008; Burusnukul et al. 2009; Weiss et al. 2010; Tang et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013; Uusimaa et al. 2013). In almost all of the reported cases, the p.Pro587Leu variant was found in cis with p.Thr251Ile as the complex allele [p.Thr251Ile; p.Pro587Leu]. In an additional two individuals, the p.Pro587Leu variant was found as part of a complex allele with a p.Pro589Leu variant. The p.Pro587Leu variant has also been reported independently in three individuals from the same family in a heterozygous state displaying a dominant pattern of inheritance. Euro et al. (2011) assessed the structure-function relationships of variants in the POLG gene and reported that the p.Pro587Leu variant constrains the Beta-hairpin loop between the IP and AID subdomains and postulate it likely reduces processivity as a result of misalignment of the ptDNA with respect to the catalytic site. DeBalsi et al. (2017) investigated the biochemical properties of purified recombinant Pol gamma p.Pro587Leu protein expressed using the baculovirus Sf9 system. Experiments demonstrated that the p.Pro587Leu variant caused a two-fold reduction in DNA binding affinity and significantly reduced thermostability. The catalytic efficiency of the p.Pro587Leu protein was reduced to approximately 32% of the wildtype level. The [p.Thr251Ile; p.Pro587Leu] variant protein demonstrated a more severe catalytic dysfunction, retaining 5% activity compared to the wild type protein and suggesting that these two variants have a synergistic effect. Based on the collective evidence the p.Pro587Leu variant is classified as pathogenic when found as part of a complex allele and of uncertain significance when found independently.
OMIM	RCV000014456	SCV000034706	pathogenic	Mitochondrial DNA depletion syndrome 4b	2004-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000508752	SCV000040907	not provided	Mitochondrial disease		no assertion provided	literature only
OMIM	RCV000186576	SCV000240152	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2004-09-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000408293	SCV000536728	pathogenic	Progressive sclerosing poliodystrophy	2016-12-12	no assertion criteria provided	research
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000508752	SCV000575915	pathogenic	Mitochondrial disease	2017-04-07	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000427845	SCV001740685	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000427845	SCV001807948	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000427845	SCV001926715	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000427845	SCV001952060	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000427845	SCV001971389	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV003458332	SCV004176863	not provided	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 04-20-2016 by Children's National Medical Center. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.