VCV000013503.21 - ClinVar

NM_001126131.2(POLG):c.752C>T (p.Thr251Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(3);Pathogenic(13);Uncertain significance(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001126131.2(POLG):c.752C>T (p.Thr251Ile)

Variation ID: 13503 Accession: VCV000013503.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 89330184 (GRCh38) [ NCBI UCSC ] 15: 89873415 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Mar 14, 2021	Nov 2, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_001126131.2:c.752C>T	NP_001119603.1:p.Thr251Ile	missense
NM_002693.2:c.752C>T	NP_002684.1:p.Thr251Ile	missense
NC_000015.10:g.89330184G>A
NC_000015.9:g.89873415G>A
NG_008218.2:g.9612C>T
LRG_765:g.9612C>T
LRG_765t1:c.752C>T	LRG_765p1:p.Thr251Ile
	P54098:p.Thr251Ile

... more HGVS ... less HGVS

Protein change

T251I

Other names

p.T251I:ACT>ATT

Canonical SPDI

NC_000015.10:89330183:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00080 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00080

The Genome Aggregation Database (gnomAD) 0.00143

Trans-Omics for Precision Medicine (TOPMed) 0.00154

The Genome Aggregation Database (gnomAD), exomes 0.00155

Exome Aggregation Consortium (ExAC) 0.00172

Links

ClinGen: CA123142 dbSNP: rs113994094 UniProtKB: P54098#VAR_023664 OMIM: 174763.0007 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
POLG		-	-	GRCh38 GRCh37	1872	3014

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	Pathogenic (2)	criteria provided, single submitter	Nov 8, 2017	RCV000014447.21
Mitochondrial DNA depletion syndrome 4B, MNGIE type	Pathogenic (1)	no assertion criteria provided	Sep 1, 2004	RCV000014448.20
Mitochondrial DNA depletion syndrome 1 (MNGIE type)	Likely pathogenic (2)	criteria provided, single submitter	Dec 3, 2017	RCV000020484.2
Progressive sclerosing poliodystrophy	Conflicting classifications of pathogenicity (8)	criteria provided, conflicting classifications	Nov 2, 2020	RCV000184009.13
not provided	Conflicting classifications of pathogenicity (8)	criteria provided, conflicting classifications	Oct 23, 2020	RCV000188641.13
not specified	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2019	RCV000194055.2
POLG-Related Spectrum Disorders	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2016	RCV000262479.1
Global developmental delay	Pathogenic (1)	criteria provided, single submitter	Jul 15, 2014	RCV000415105.1
Seizures	Pathogenic (1)	criteria provided, single submitter	Oct 9, 2018	RCV000716828.1
Mitochondrial DNA depletion syndrome 4B, MNGIE type Progressive sclerosing poliodystrophy	Pathogenic (1)	criteria provided, single submitter	-	RCV001004407.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 12, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Mitochondrial DNA depletion syndrome 4A (Alpers type) Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory,Courtagen Life Sciences Accession: SCV000236523.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	POLG-Related Spectrum Disorders Affected status: unknown Allele origin: germline	Illumina Clinical Services Laboratory,Illumina Accession: SCV000394298.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (15) PubMed: 21880868‚ 15349879‚ 12297582‚ 12825077‚ 23665194‚ 23783014‚ 20513108‚ 18487244‚ 16621917‚ 25660390‚ 19189930‚ 18546365‚ 24508722‚ 22616202‚ 12210792 Comment: 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 … (more) 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; GÃ¡ti 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. (less)
Pathogenic (Jul 15, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Global developmental delay Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics,University Medical Centre Ljubljana Accession: SCV000492822.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Uncertain significance (Apr 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics Accession: SCV000511806.2 First in ClinVar: Mar 08, 2017 Last updated: Nov 04, 2017
Pathogenic (Nov 08, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, Klinikum rechts der Isar Accession: SCV000680344.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Likely pathogenic (Dec 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 (MNGIE type) Affected status: unknown Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746436.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Age: 20-29 years Sex: female Geographic origin: Iran
Pathogenic (Oct 05, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	EGL Genetic Diagnostics, Eurofins Clinical Diagnostics Accession: SCV000332083.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG Number of individuals with the variant: 22 Sex: mixed
Likely pathogenic (Apr 06, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories Accession: SCV000884405.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018
Uncertain significance (Oct 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: germline	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine Accession: SCV000886920.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 15349879 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 16, 2019)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242264.11 First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019	Comment: 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 … (more) 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. (less)
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139686.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Apr 16, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Inc Accession: SCV001145168.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (21) PubMed: 27538604‚ 28130605‚ 26104464‚ 29474836‚ 28154168‚ 19578034‚ 18828154‚ 21138766‚ 23324391‚ 23665194‚ 20385918‚ 23804100‚ 12210792‚ 12707443‚ 12825077‚ 15349879‚ 15689359‚ 25660390‚ 26337858‚ 26468652‚ 25940035 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Mitochondrial DNA depletion syndrome 4B, MNGIE type Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163401.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (Jul 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genetic Services Laboratory,University of Chicago Accession: SCV000248561.2 First in ClinVar: Oct 05, 2015 Last updated: Jun 12, 2020
Uncertain significance (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440553.1 First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020	Comment: This variant was identified as compound heterozygous.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446809.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Microcephaly (present) , Muscular hypotonia (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Developmental regression (present) , Myopathy (present) , Muscular dystrophy (present) … (more) Microcephaly (present) , Muscular hypotonia (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Developmental regression (present) , Myopathy (present) , Muscular dystrophy (present) , Cardiorespiratory arrest (present) , Developmental stagnation (present) (less) Sex: male
Pathogenic (Oct 09, 2018)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (3/2017)) Method: clinical testing	Seizures Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000847672.2 First in ClinVar: Nov 08, 2018 Last updated: Nov 08, 2018	Publications: PubMed (4) PubMed: 22616202‚ 23665194‚ 25585994‚ 28154168 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Likely pathogenic (Jan 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial dna depletion syndrome 4a (alpers type) Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448886.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1 Clinical Features: Muscular hypotonia (present) , Laryngomalacia (present) , Autistic disorder of childhood onset (present) , Global developmental delay (present) , Hernia (present) , Generalized hypotonia (present) … (more) Muscular hypotonia (present) , Laryngomalacia (present) , Autistic disorder of childhood onset (present) , Global developmental delay (present) , Hernia (present) , Generalized hypotonia (present) , Autistic behavior (present) , Failure to thrive (present) , Abnormal facial shape (present) , Esotropia (present) , Oligohydramnios (present) , Growth delay (present) , Strabismus (present) , Cryptorchidism (present) , Abnormality of the atrial septum (present) , Dysphagia (present) , Retrognathia (present) , Infantile muscular hypotonia (present) (less) Sex: male
Pathogenic (Jul 14, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: yes Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481357.2 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (Praxis fuer Humangenetik Tuebingen - Variant Classification Criteria) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Praxis fuer Humangenetik Tuebingen Accession: SCV001149577.5 First in ClinVar: Feb 03, 2020 Last updated: Nov 28, 2020	Number of individuals with the variant: 8
Uncertain significance (Nov 02, 2020)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: germline	Invitae Accession: SCV000543870.7 First in ClinVar: Dec 06, 2016 Last updated: Mar 14, 2021	Publications: PubMed (8) PubMed: 28492532‚ 14635118‚ 15349879‚ 16621917‚ 19189930‚ 21880868‚ 25660390‚ 12210792 Comment: This sequence change replaces threonine with isoleucine at codon 251 of the POLG protein (p.Thr251Ile). The threonine residue is weakly conserved and there is a … (more) This sequence change replaces threonine with isoleucine at codon 251 of the POLG protein (p.Thr251Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases, including a homozygous individual (rs113994094, ExAC 0.3%). This variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Pro587Leu) variant (PMID: 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). In many of these cases, these two variants in cis were observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual. These findings are consistent with autosomal recessive inheritance, and suggest that these variants in cis contribute to disease. Furthermore, these two variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879). ClinVar contains an entry for this variant (Variation ID: 13503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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, it has also been observed in unaffected individuals and in population databases. Furthermore, because it almost always occurs in cis with p.Pro587Leu, 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. (less)
pathologic (Oct 11, 2012)	no assertion criteria provided Method: curation	POLG-Related Disorders Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000040921.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Comment: Converted during submission to Pathogenic.
Pathogenic (Sep 01, 2004)	no assertion criteria provided Method: literature only	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034697.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 27, 2016	Publications: PubMed (4) PubMed: 12210792‚ 12297582‚ 12825077‚ 15349879 Comment on evidence: For discussion of the thr251-to-ile (T251I) mutation in the POLG gene that was found in compound heterozygous state in a patient with autosomal recessive PEO … (more) For discussion of the thr251-to-ile (T251I) mutation in the POLG gene that was found in compound heterozygous state in a patient with autosomal recessive PEO (PEOB1; 258450) by Lamantea et al. (2002), see 174763.0006. In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662), manifest as a neurogastrointestinal encephalopathy syndrome (Vissing et al., 2002), Van Goethem et al. (2003) identified 3 mutations in the POLG gene: a 752C-T transition in exon 3, resulting in a thr251-to-ile (T251I) substitution, a 1760C-T transition in exon 10, resulting in a pro587-to-leu substitution (P587L; 174763.0011), and a 2591A-T transversion in exon 16, resulting in an asn864-to-ser substitution (N864S; 174763.0012). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. Lamantea and Zeviani (2004) identified the T251I mutation and the P587L mutation on the same allele in 3 families with autosomal recessive PEO (PEOB1; 258450); each of the families was compound heterozygous for another POLG1 mutation in trans with the 2 cis alleles. (less)
Pathogenic (Sep 01, 2004)	no assertion criteria provided Method: literature only	MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034698.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 27, 2016	Publications: PubMed (4) PubMed: 12210792‚ 12297582‚ 12825077‚ 15349879 Comment on evidence: For discussion of the thr251-to-ile (T251I) mutation in the POLG gene that was found in compound heterozygous state in a patient with autosomal recessive PEO … (more) For discussion of the thr251-to-ile (T251I) mutation in the POLG gene that was found in compound heterozygous state in a patient with autosomal recessive PEO (PEOB1; 258450) by Lamantea et al. (2002), see 174763.0006. In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662), manifest as a neurogastrointestinal encephalopathy syndrome (Vissing et al., 2002), Van Goethem et al. (2003) identified 3 mutations in the POLG gene: a 752C-T transition in exon 3, resulting in a thr251-to-ile (T251I) substitution, a 1760C-T transition in exon 10, resulting in a pro587-to-leu substitution (P587L; 174763.0011), and a 2591A-T transversion in exon 16, resulting in an asn864-to-ser substitution (N864S; 174763.0012). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. Lamantea and Zeviani (2004) identified the T251I mutation and the P587L mutation on the same allele in 3 families with autosomal recessive PEO (PEOB1; 258450); each of the families was compound heterozygous for another POLG1 mutation in trans with the 2 cis alleles. (less)
Pathogenic (Dec 12, 2016)	no assertion criteria provided Method: research	Progressive sclerosing poliodystrophy Affected status: yes Allele origin: maternal	Division of Human Genetics,Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536729.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (5) PubMed: 12210792‚ 23665194‚ 22616202‚ 23783014‚ 20513108
Likely pathogenic (Mar 08, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Genetic Testing Laboratories,Mayo Clinic Accession: SCV000802095.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018
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Comment:

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; GÃ¡ti 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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

This sequence change replaces threonine with isoleucine at codon 251 of the POLG protein (p.Thr251Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases, including a homozygous individual (rs113994094, ExAC 0.3%). This variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Pro587Leu) variant (PMID: 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). In many of these cases, these two variants in cis were observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual. These findings are consistent with autosomal recessive inheritance, and suggest that these variants in cis contribute to disease. Furthermore, these two variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879). ClinVar contains an entry for this variant (Variation ID: 13503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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, it has also been observed in unaffected individuals and in population databases. Furthermore, because it almost always occurs in cis with p.Pro587Leu, 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
POLG-Related Disorders.	Adam MP	-	2024	PMID: 20301791
Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations.	Masingue M	Mitochondrion	2019	PMID: 29474836
Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations.	DeBalsi KL	The Journal of biological chemistry	2017	PMID: 28154168
Novel POLG mutations and variable clinical phenotypes in 13 Italian patients.	Da Pozzo P	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2017	PMID: 28130605
The wide POLG-related spectrum: An integrated view.	Béreau M	Journal of the neurological sciences	2016	PMID: 27538604
Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease.	Chrysostomou A	Neuropathology and applied neurobiology	2016	PMID: 26337858
The spectrum of epilepsy caused by POLG mutations.	Janssen W	Acta neurologica Belgica	2016	PMID: 26104464
Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.	Singh B	PloS one	2015	PMID: 26468652
Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes.	Komulainen T	JIMD reports	2015	PMID: 25940035
The in cis T251I and P587L POLG1 base changes: description of a new family and literature review.	Scuderi C	Neuromuscular disorders : NMD	2015	PMID: 25660390
Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson's disease.	Gui YX	Parkinsonism & related disorders	2015	PMID: 25585994
Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.	Farnum GA	Biochimica et biophysica acta	2014	PMID: 24508722
The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons.	Reeve A	The Journal of neuroscience : the official journal of the Society for Neuroscience	2013	PMID: 23804100
Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure.	Helbling D	Journal of pediatric gastroenterology and nutrition	2013	PMID: 23783014
The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders.	Dames S	The Journal of molecular diagnostics : JMD	2013	PMID: 23665194
POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome.	Cheldi A	BMC neurology	2013	PMID: 23324391
Sensory ataxic neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO). Two case reports.	Gáti I	Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology	2011	PMID: 22616202
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.	Tang S	Journal of medical genetics	2011	PMID: 21880868
POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts.	Stewart JD	Biochimica et biophysica acta	2011	PMID: 21138766
Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) in late life due to compound heterozygous POLG mutations.	Weiss MD	Muscle & nerve	2010	PMID: 20513108
Is it ADEM, POLG, or both?	Harris MO	Archives of neurology	2010	PMID: 20385918
The unfolding clinical spectrum of POLG mutations.	Blok MJ	Journal of medical genetics	2009	PMID: 19578034
Phenotypic variations in 3 children with POLG1 mutations.	Burusnukul P	Journal of child neurology	2009	PMID: 19189930
Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion.	Taanman JW	Human mutation	2009	PMID: 18828154
Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.	Wong LJ	Human mutation	2008	PMID: 18546365
Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.	Ashley N	Human molecular genetics	2008	PMID: 18487244
Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.	Horvath R	Brain : a journal of neurology	2006	PMID: 16621917
Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA.	Ferrari G	Brain : a journal of neurology	2005	PMID: 15689359
Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene.	Lamantea E	Annals of neurology	2004	PMID: 15349879
POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions.	Di Fonzo A	Human mutation	2003	PMID: 14635118
Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.	Van Goethem G	European journal of human genetics : EJHG	2003	PMID: 12825077
Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO).	Agostino A	Neurology	2003	PMID: 12707443
Multiple mtDNA deletions with features of MNGIE.	Vissing J	Neurology	2002	PMID: 12297582
Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.	Lamantea E	Annals of neurology	2002	PMID: 12210792
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG	-	-	-	-
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Text-mined citations for rs113994094 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Mar 18, 2022

ClinVar Genomic variation as it relates to human health

NM_001126131.2(POLG):c.752C>T (p.Thr251Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113994094 ...