NM_002693.2(POLG):c.1790G>A (p.Arg597Gln) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 1, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000699074.1

Allele description [Variation Report for NM_002693.2(POLG):c.1790G>A (p.Arg597Gln)]

NM_002693.2(POLG):c.1790G>A (p.Arg597Gln)

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.2(POLG):c.1790G>A (p.Arg597Gln)
HGVS:
  • NC_000015.10:g.89325609C>T
  • NG_008218.2:g.14187G>A
  • NM_002693.2:c.1790G>A
  • NP_002684.1:p.Arg597Gln
  • LRG_765t1:c.1790G>A
  • LRG_765:g.14187G>A
  • LRG_765p1:p.Arg597Gln
  • NC_000015.9:g.89868840C>T
Protein change:
R597Q
Molecular consequence:
  • NM_002693.2:c.1790G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
Alpers Syndrome; Mitochondrial DNA depletion syndrome 4A (Alpers type); Alpers-Huttenlocher Syndrome
Identifiers:
MedGen: C0205710; Orphanet: 726; OMIM: 203700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000827769Invitaecriteria provided, single submitter
Uncertain significance
(Feb 26, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000887148Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Oct 1, 2018)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders.

Saneto RP, Lee IC, Koenig MK, Bao X, Weng SW, Naviaux RK, Wong LJ.

Seizure. 2010 Apr;19(3):140-6. doi: 10.1016/j.seizure.2010.01.002. Epub 2010 Feb 6.

PubMed [citation]
PMID:
20138553
PMCID:
PMC3099441

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.

Stewart JD, Tennant S, Powell H, Pyle A, Blakely EL, He L, Hudson G, Roberts M, du Plessis D, Gow D, Mewasingh LD, Hanna MG, Omer S, Morris AA, Roxburgh R, Livingston JH, McFarland R, Turnbull DM, Chinnery PF, Taylor RW.

J Med Genet. 2009 Mar;46(3):209-14. doi: 10.1136/jmg.2008.058180.

PubMed [citation]
PMID:
19251978
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000827769.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces arginine with glutamine at codon 597 of the POLG protein (p.Arg597Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLG-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg597Trp) has been reported in individuals affected with POLG-related conditions (PMID: 20138553, 19251978). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicine, SCV000887148.1

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

Description

The NM_002693.2:c.1790G>A (NP_002684.1:p.Arg597Gln) [GRCH38: NC_000015.10:g.89325609C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

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

Last Updated: Mar 30, 2019

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