VCV000065665.79 - ClinVar

NM_002693.3(POLG):c.1550G>T (p.Gly517Val)

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.

(24)

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
Uncertain significance(3); Benign(7); Likely benign(7)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002693.3(POLG):c.1550G>T (p.Gly517Val)

Variation ID: 65665 Accession: VCV000065665.79

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 89326947 (GRCh38) [ NCBI UCSC ] 15: 89870178 (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	Oct 1, 2013	Dec 22, 2024	Nov 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002693.3:c.1550G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002684.1:p.Gly517Val	missense
NM_001126131.2:c.1550G>T	NP_001119603.1:p.Gly517Val	missense
NC_000015.10:g.89326947C>A
NC_000015.9:g.89870178C>A
NG_008218.2:g.12849G>T
LRG_765:g.12849G>T
LRG_765t1:c.1550G>T	LRG_765p1:p.Gly517Val
	P54098:p.Gly517Val

... more HGVS ... less HGVS

Protein change

G517V

Other names

p.G517V:GGG>GTG

Canonical SPDI

NC_000015.10:89326946:C: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.

0.00379 (A)

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

1000 Genomes Project 0.00379

1000 Genomes Project 30x 0.00422

Exome Aggregation Consortium (ExAC) 0.00475

The Genome Aggregation Database (gnomAD), exomes 0.00477

Trans-Omics for Precision Medicine (TOPMed) 0.00493

The Genome Aggregation Database (gnomAD) 0.00516

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00600

Links

ClinGen: CA204012 UniProtKB: P54098#VAR_058879 dbSNP: rs61752783 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	2039	3051

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.
Mitochondrial disease	not provided (1)	no classification provided	-	RCV000055881.11
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 24, 2019	RCV000118011.27
Idiopathic camptocormia	Pathogenic (1)	no assertion criteria provided	Jan 1, 2012	RCV000186556.9
not provided	Benign/Likely benign (8)	criteria provided, multiple submitters, no conflicts	Nov 1, 2024	RCV000223970.55
Progressive sclerosing poliodystrophy	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000229511.26
Mitochondrial DNA depletion syndrome 4b Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Progressive sclerosing poliodystrophy Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	Uncertain significance (1)	criteria provided, single submitter	May 18, 2022	RCV000768289.10
POLG-Related Spectrum Disorders	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001117969.12
Tip-toe gait	Uncertain significance (1)	criteria provided, single submitter	Feb 4, 2021	RCV001352901.10
Inborn genetic diseases	Likely benign (1)	criteria provided, single submitter	Jul 2, 2018	RCV002311532.9
Hereditary spastic paraplegia	Benign (1)	criteria provided, single submitter	Jan 22, 2021	RCV001847644.11
POLG-related disorder	Benign (1)	no assertion criteria provided	Jan 10, 2020	RCV003985725.2
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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.
Likely Benign (May 19, 2016)	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: SCV000281444.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Benign (Sep 07, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000843315.1 First in ClinVar: Oct 19, 2018 Last updated: Oct 19, 2018	Publications: PubMed (16) PubMed: 16621917‚ 17452231‚ 18546365‚ 19189930‚ 19578034‚ 19752458‚ 19815814‚ 20803511‚ 28130605‚ 22647225‚ 20227526‚ 21856450‚ 21880868‚ 22727047‚ 23808377‚ 27271921
Benign (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: SCV000887270.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (1) PubMed: 16621917 Comment: The NM_002693.2:c.1550G>T (NP_002684.1:p.Gly517Val) [GRCH38: NC_000015.10:g.89326947C>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been … (more) The NM_002693.2:c.1550G>T (NP_002684.1:p.Gly517Val) [GRCH38: NC_000015.10:g.89326947C>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. (less)
Likely benign (Oct 05, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967286.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (6) PubMed: 21856450‚ 18546365‚ 16621917‚ 19189930‚ 19815814‚ 28130605 Comment: The c.1550G>T (p.Gly517Val) variant is classified as likely benign due to its fr equency in the general population. This variant has been identified in 0.73% … (more) The c.1550G>T (p.Gly517Val) variant is classified as likely benign due to its fr equency in the general population. This variant has been identified in 0.73% (92 5/126620) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/), including 3 homozygotes. In addition, function al studies demonstrate an effect indistinguishable from wild type. (less) Number of individuals with the variant: 1
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	POLG-Related Spectrum Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001276215.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 21856450‚ 16621917 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000152329.4 First in ClinVar: May 17, 2014 Last updated: Jun 15, 2020
Uncertain significance (May 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Mitochondrial DNA depletion syndrome 4b Progressive sclerosing poliodystrophy Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898901.2 First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023	Comment: POLG NM_002693.2 exon 8 p.Gly517Val (c.1550G>T): This variant is a well reported and controversial variant in the literature, identified in several individuals with POLG related … (more) POLG NM_002693.2 exon 8 p.Gly517Val (c.1550G>T): This variant is a well reported and controversial variant in the literature, identified in several individuals with POLG related disease in the heterozygous, compound and double heterozygous state, many of which are reported with significantly variable phenotypes (Horvath 2006 PMID:16621917, Wong 2008 PMID:18546365, Tang 2011 PMID:21880868, Staropoli 2012 PMID:22727047, Gailey 2013 PMID:23808377, Woodbridge 2013 PMID:22647225, DaPozzo 2017 PMID:28130605). However, this variant is present in 0.7% (925/126620) of European alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752783). This variant is present in ClinVar with multiple different classifications, including several Likely Benign/Benign entries (Variation ID:65665). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In addition, functional studies suggest that this variant retains 80-90% of activity relative to wild-type (Kasiviswanathan 2011 PMID:21856450). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is too conflicting for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287664.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024
Likely benign (Jul 02, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000846912.4 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (May 25, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242169.8 First in ClinVar: Aug 07, 2015 Last updated: Nov 10, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Sep 26, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111915.8 First in ClinVar: Jan 17, 2014 Last updated: Nov 10, 2017	Publications: PubMed (2) PubMed: 16621917‚ 21880868 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: 2 Zygosity: Single Heterozygote Sex: mixed
Likely benign (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: SCV001139682.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 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: SCV001440547.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Benign (Jan 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002105553.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Benign (Nov 09, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884403.3 First in ClinVar: Feb 17, 2019 Last updated: Feb 20, 2024
Uncertain significance (Feb 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tip-toe gait Affected status: yes Allele origin: unknown	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV001547509.2 First in ClinVar: Mar 28, 2021 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 37091313 Comment: We conducted a clinical examination of patients about toe walking. The POLG c.1550G>T was detected in 2 patients. We also examined a control group of … (more) We conducted a clinical examination of patients about toe walking. The POLG c.1550G>T was detected in 2 patients. We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. (less) Number of individuals with the variant: 2 Clinical Features: Hypotonia (present) Zygosity: Single Heterozygote Age: 4-8 years Sex: mixed Method: Gene panel analysis
Likely benign (Nov 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000608735.32 First in ClinVar: Oct 30, 2017 Last updated: Dec 22, 2024	Comment: POLG: BP4, BS2 Number of individuals with the variant: 75
Pathogenic (Jan 01, 2012)	no assertion criteria provided Method: literature only	Camptocormia Myopathy (camptocormia) Affected status: yes Allele origin: unknown	Department of Neurology, University Hospital of Strasbourg Accession: SCV000240098.1 First in ClinVar: Jul 30, 2015 Last updated: Jul 30, 2015	Publications: PubMed (1) PubMed: 16621917 Number of individuals with the variant: 2 Clinical Features: Camptocormia (present) , Limb-girdle myopathy (present) Indication for testing: Camptocormia Family history: yes Age: 50-60 years Sex: mixed Ethnicity/Population group: Caucasianss Geographic origin: France Tissue: Muscle
Likely benign (Mar 08, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000802090.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741966.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (Jan 10, 2020)	no assertion criteria provided Method: clinical testing	POLG-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004787329.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927575.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001969779.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (-)	no classification provided Method: literature only	Mitochondrial disease Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086887.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 21856450‚ 20301791 BookShelf: NBK26471 BookShelf: NBK26471
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Comment:

The NM_002693.2:c.1550G>T (NP_002684.1:p.Gly517Val) [GRCH38: NC_000015.10:g.89326947C>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.

Comment:

The c.1550G>T (p.Gly517Val) variant is classified as likely benign due to its fr equency in the general population. This variant has been identified in 0.73% (92 5/126620) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/), including 3 homozygotes. In addition, function al studies demonstrate an effect indistinguishable from wild type.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

POLG NM_002693.2 exon 8 p.Gly517Val (c.1550G>T): This variant is a well reported and controversial variant in the literature, identified in several individuals with POLG related disease in the heterozygous, compound and double heterozygous state, many of which are reported with significantly variable phenotypes (Horvath 2006 PMID:16621917, Wong 2008 PMID:18546365, Tang 2011 PMID:21880868, Staropoli 2012 PMID:22727047, Gailey 2013 PMID:23808377, Woodbridge 2013 PMID:22647225, DaPozzo 2017 PMID:28130605). However, this variant is present in 0.7% (925/126620) of European alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752783). This variant is present in ClinVar with multiple different classifications, including several Likely Benign/Benign entries (Variation ID:65665). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In addition, functional studies suggest that this variant retains 80-90% of activity relative to wild-type (Kasiviswanathan 2011 PMID:21856450). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is too conflicting for disease classification. Therefore, the clinical significance of this variant is uncertain.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

We conducted a clinical examination of patients about toe walking. The POLG c.1550G>T was detected in 2 patients. We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

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
NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly.	Pomarino D	Global medical genetics	2023	PMID: 37091313
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
Diagnostic value of MRS-quantified brain tissue lactate level in identifying children with mitochondrial disorders.	Lunsing RJ	European radiology	2017	PMID: 27271921
Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings.	Gaily E	Epilepsia	2013	PMID: 23808377
POLG mutations in Australian patients with mitochondrial disease.	Woodbridge P	Internal medicine journal	2013	PMID: 22647225
An atypical case of neuronal ceroid lipofuscinosis with co-inheritance of a variably penetrant POLG1 mutation.	Staropoli JF	BMC medical genetics	2012	PMID: 22727047
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.	Tang S	Journal of medical genetics	2011	PMID: 21880868
Biochemical analysis of the G517V POLG variant reveals wild-type like activity.	Kasiviswanathan R	Mitochondrion	2011	PMID: 21856450
POLG, but not PEO1, is a frequent cause of cerebellar ataxia in Central Europe.	Schicks J	Movement disorders : official journal of the Movement Disorder Society	2010	PMID: 20803511
Marked mitochondrial DNA depletion associated with a novel SUCLG1 gene mutation resulting in lethal neonatal acidosis, multi-organ failure, and interrupted aortic arch.	Rivera H	Mitochondrion	2010	PMID: 20227526
Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease.	Hopkins SE	Journal of child neurology	2010	PMID: 19815814
Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations.	Schulte C	Neurology	2009	PMID: 19752458
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
Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.	Wong LJ	Human mutation	2008	PMID: 18546365
Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood.	Sarzi E	The Journal of pediatrics	2007	PMID: 17452231
Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.	Horvath R	Brain : a journal of neurology	2006	PMID: 16621917
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG	-	-	-	-
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Text-mined citations for rs61752783 ...

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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_002693.3(POLG):c.1550G>T (p.Gly517Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61752783 ...