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

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 18, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000768289.10

Allele description [Variation Report for NM_002693.3(POLG):c.1550G>T (p.Gly517Val)]

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

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.3(POLG):c.1550G>T (p.Gly517Val)
Other names:
p.G517V:GGG>GTG
HGVS:
  • NC_000015.10:g.89326947C>A
  • NG_008218.2:g.12849G>T
  • NM_001126131.2:c.1550G>T
  • NM_002693.3:c.1550G>TMANE SELECT
  • NP_001119603.1:p.Gly517Val
  • NP_002684.1:p.Gly517Val
  • LRG_765t1:c.1550G>T
  • LRG_765:g.12849G>T
  • LRG_765p1:p.Gly517Val
  • NC_000015.9:g.89870178C>A
  • NM_001126131.1:c.1550G>T
  • NM_002693.2:c.1550G>T
  • P54098:p.Gly517Val
Protein change:
G517V
Links:
UniProtKB: P54098#VAR_058879; dbSNP: rs61752783
NCBI 1000 Genomes Browser:
rs61752783
Molecular consequence:
  • NM_001126131.2:c.1550G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.1550G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
ALPERS PROGRESSIVE INFANTILE POLIODYSTROPHY; NEURONAL DEGENERATION OF CHILDHOOD WITH LIVER DISEASE, PROGRESSIVE; Alpers disease; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008758; MedGen: C0205710; Orphanet: 726; OMIM: 203700
Name:
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (PEOA1)
Synonyms:
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 1
Identifiers:
MONDO: MONDO:0024528; MedGen: C1834846; OMIM: 157640
Name:
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (PEOB1)
Synonyms:
Cerebellar ataxia infantile with progressive external ophthalmoplegia; Progressive external ophthalmoplegia, autosomal recessive 1
Identifiers:
MONDO: MONDO:0009783; MedGen: C4225153; Orphanet: 254886; OMIM: 258450
Name:
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO)
Synonyms:
SENSORY ATAXIC NEUROPATHY WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Epilepsy, progressive myoclonic, type 5
Identifiers:
MONDO: MONDO:0011835; MedGen: C1843851; OMIM: 607459
Name:
Mitochondrial DNA depletion syndrome 4b
Synonyms:
MNGIE, POLG-RELATED; Mitochondrial Neurogastrointestinal Encephalopathy Disease, POLG-Related; Mitochondrial DNA depletion syndrome 4B, MNGIE type
Identifiers:
MONDO: MONDO:0013350; MedGen: C3150914; Orphanet: 298; OMIM: 613662

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000898901Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(May 18, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000898901.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 26, 2025