Submissions for variant NM_002693.3(POLG):c.752C>T (p.Thr251Ile)

gnomAD frequency: 0.00143  dbSNP: rs113994094

Total submissions: 44

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000184009	SCV000236523	pathogenic	Progressive sclerosing poliodystrophy	2014-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000188641	SCV000242264	pathogenic	not provided	2019-01-16	criteria provided, single submitter	clinical testing	The T251I missense variant in the POLG gene has been reported previously in association with several POLG-related disorders (Human DNA Polymerase Gamma Mutation Database). The T251I missense variant is typically found on the same allele (in cis) with the P587L variant and together they account for approximately 6% of disease-causing alleles in the POLG gene (Tang et al., 2011); however, the P587L variant was not observed in this patient. The T251I variant is observed in 195/66,122 (0.3%) alleles from individuals of European background, including 1 unrelated homozygous individual in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T251I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution alters at a poorly conserved residue predicted to be in the exonuclease domain. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret T251I as a pathogenic variant.
Genetic Services Laboratory, University of Chicago	RCV000194055	SCV000248561	pathogenic	not specified	2019-07-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000188641	SCV000332083	pathogenic	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000262479	SCV000394298	pathogenic	POLG-Related Spectrum Disorders	2016-06-14	criteria provided, single submitter	clinical testing	The c.752C>T (p.Thr251Ile) variant is well described in the literature and has been reported across 11 studies in which it has been found in 36 individuals affected with POLG-related spectrum disorders covering a wide range of phenotypes (Van Goethem 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; Gáti et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013). In all but one of the reported cases, the p.Thr251Ile variant has been found in cis with p.Pro587Leu as the complex allele [p.Thr251Ile; p.Pro587Leu]. Twenty-four of the reported cases are compound heterozygotes with a third variant in trans to the complex allele, five cases are homozygous for the complex allele and six are heterozygotes. The one instance where the p.Thr251Ile variant was found independently was in a compound heterozygote state with another missense variant in one individual (Gati et al. 2011). The complex allele has been found in 5/2040 control alleles and the p.Thr251Ile variant alone is reported at a frequency of 0.00337 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Thr251Ile variant is classified as pathogenic for POLG-related spectrum disorders when found as part of the complex allele and of unknown significance but suspicious for pathogenicity for POLG-related spectrum disorders when found independently.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415105	SCV000492822	pathogenic	Global developmental delay	2014-07-15	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188641	SCV000511806	uncertain significance	not provided	2017-04-17	criteria provided, single submitter	clinical testing
Invitae	RCV000184009	SCV000543870	pathogenic	Progressive sclerosing poliodystrophy	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 251 of the POLG protein (p.Thr251Ile). This variant is present in population databases (rs113994094, 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 variant, p.Pro587Leu (PMID: 12210792, 15349879, 18546365, 19251978, 19566497, 19578034, 30423451, 30936349, 33396418). 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. Additionally, the p.Thr251Ile variant has been observed independent from the p.Pro587Leu variant in individual(s) with autosomal recessive POLG-related conditions (PMID: 12707443, 22616202, 23921535). ClinVar contains an entry for this variant (Variation ID: 13503). 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 not expected to disrupt POLG protein function. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar	RCV000014447	SCV000680344	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	RCV000020484	SCV000746436	likely pathogenic	Mitochondrial DNA depletion syndrome 1	2017-12-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313708	SCV000847672	pathogenic	Inborn genetic diseases	2018-10-09	criteria provided, single submitter	clinical testing	The p.T251I pathogenic mutation (also known as c.752C>T), located in coding exon 2 of the POLG gene, results from a C to T substitution at nucleotide position 752. The threonine at codon 251 is replaced by isoleucine, an amino acid with similar properties. This mutation has been reported to occur almost exclusively in cis with p.P587L (c.1760C>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, possible Kearns-Sayre syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability and various other POLG-deficiency symptoms (Dames S et al. J Mol Diagn, 2013 Jul;15:526-34; 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.P587L (c.1760C>T) in an individual with Parkinson disease without another POLG alteration and in another individual who also carried POLG p.G848S (phase was not confirmed) with sensory ataxic neuropathy, dysarthria/dysphagia and external ophthalmoplegia (SANDO) (Gáti I et al. Acta Myol, 2011 Dec;30:188-90; Gui YX et al. Parkinsonism Relat. Disord., 2015 Mar;21:282-6). In addition, biochemical characterization of T251I 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 T251I alone (DeBalsi KL et al. J. Biol. Chem., 2017 03;292:4198-4209). Based on the supporting evidence, p.T251I is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000188641	SCV000884405	likely pathogenic	not provided	2018-04-06	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000184009	SCV000886920	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.752C>T (NP_002684.1:p.Thr251Ile) [GRCH38: NC_000015.10:g.89330184G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Mendelics	RCV000184009	SCV001139686	uncertain significance	Progressive sclerosing poliodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000188641	SCV001145168	pathogenic	not provided	2019-04-16	criteria provided, single submitter	clinical testing	Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
CeGaT Center for Human Genetics Tuebingen	RCV000188641	SCV001149577	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004407	SCV001163401	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000184009	SCV001440553	uncertain significance	Progressive sclerosing poliodystrophy	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000188641	SCV001446809	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000184009	SCV001448886	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	RCV001642225	SCV001519176	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2021-01-04	criteria provided, single submitter	research
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813985	SCV001755619	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001678594	SCV001810055	pathogenic	Tip-toe gait	2021-02-10	criteria provided, single submitter	clinical testing	The variant c.752C> T p. (Thr251Ile) [dbSNP: rs113994094, frequency: 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	RCV000014448	SCV001950112	uncertain significance	Mitochondrial DNA depletion syndrome 4b	2021-07-27	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_001126131.2:c.1760C>T.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000188641	SCV002011120	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
DASA	RCV001813742	SCV002061172	pathogenic	POLG-related disorders	2022-01-05	criteria provided, single submitter	clinical testing	The c.752C>T;p.(Thr251Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 13503; OMIM 174763.0007; PMID: 12210792; 12825077; 15349879; 26224072; 26742794PS4. The p.(Thr251Ile) was detected in trans with a pathogenic variant (PMID: 20385918) - PM3. 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	RCV001847602	SCV002104887	likely pathogenic	Hereditary spastic paraplegia	2021-11-22	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000188641	SCV002503522	likely pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000014448	SCV002512298	pathogenic	Mitochondrial DNA depletion syndrome 4b	2022-02-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001813742	SCV002568171	pathogenic	POLG-related disorders	2022-06-02	criteria provided, single submitter	clinical testing	PS3, PM3_Very Strong, PP1
3billion	RCV000014447	SCV002572623	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. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013503). The variant was observed in cis with NM_002693.3:c.1760C>T (p.Pro587Leu) 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.
Institute of Human Genetics, University Hospital Muenster	RCV002287334	SCV002578053	uncertain significance	Stroke	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,BP1
MGZ Medical Genetics Center	RCV000014447	SCV002581641	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-07-29	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000014448	SCV002583555	uncertain significance	Mitochondrial DNA depletion syndrome 4b	2021-02-13	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 3 of the POLG gene that results in the amino acid substitution of Isoleucine for Threonine at codon251 was detected. The observed variant c.752C>T (p.Thr251lle) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases respectively. The in silico prediction of the variant is benign 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 a variant of uncertain significance.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000014447	SCV002587018	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2021-07-27	criteria provided, single submitter	research
Genetic Medico-Diagnostic Laboratory Genica	RCV002319423	SCV002605539	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 0.1535% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. The variant has conflicting predictions of pathogenicity, based on in silico data analysis (Polyphen-2 and SIFT - benign, Mutation-Taster - disease causing), with the position being poorly conserved and threonine and isoleucine having moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.1760C>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	RCV001813742	SCV003804677	likely pathogenic	POLG-related disorders	2022-12-19	criteria provided, single submitter	clinical testing	_x000D_Criteria applied: PS3, PS4_SUP, PP1
PerkinElmer Genomics	RCV000188641	SCV003818490	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing
OMIM	RCV000014447	SCV000034697	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2004-09-01	no assertion criteria provided	literature only
OMIM	RCV000014448	SCV000034698	pathogenic	Mitochondrial DNA depletion syndrome 4b	2004-09-01	no assertion criteria provided	literature only
GeneReviews	RCV002272019	SCV000040921	not provided	Mitochondrial disease		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000184009	SCV000536729	pathogenic	Progressive sclerosing poliodystrophy	2016-12-12	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000188641	SCV000802095	likely pathogenic	not provided	2016-03-08	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000184009	SCV001760354	likely pathogenic	Progressive sclerosing poliodystrophy		no assertion criteria provided	clinical testing