NM_002693.2(POLG):c.3139C>T (p.Arg1047Trp) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely 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:
RCV000633548.2

Allele description [Variation Report for NM_002693.2(POLG):c.3139C>T (p.Arg1047Trp)]

NM_002693.2(POLG):c.3139C>T (p.Arg1047Trp)

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.3139C>T (p.Arg1047Trp)
Other names:
p.R1047W:CGG>TGG
HGVS:
  • NC_000015.10:g.89319065G>A
  • NG_008218.2:g.20731C>T
  • NM_002693.2:c.3139C>T
  • NP_002684.1:p.Arg1047Trp
  • LRG_765t1:c.3139C>T
  • LRG_765:g.20731C>T
  • LRG_765p1:p.Arg1047Trp
  • NC_000015.9:g.89862296G>A
Protein change:
R1047W
Links:
dbSNP: rs181860632
NCBI 1000 Genomes Browser:
rs181860632
Molecular consequence:
  • NM_002693.2:c.3139C>T - 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
SCV000754794Invitaecriteria provided, single submitter
Uncertain significance
(Jun 12, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000887120Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Oct 1, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol γ.

Euro L, Farnum GA, Palin E, Suomalainen A, Kaguni LS.

Nucleic Acids Res. 2011 Nov;39(21):9072-84. doi: 10.1093/nar/gkr618. Epub 2011 Aug 8. Review.

PubMed [citation]
PMID:
21824913
PMCID:
PMC3241644

High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency.

Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK.

Nat Genet. 2010 Oct;42(10):851-8. doi: 10.1038/ng.659. Epub 2010 Sep 5.

PubMed [citation]
PMID:
20818383
PMCID:
PMC2977978
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000754794.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with tryptophan at codon 1047 of the POLG protein (p.Arg1047Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs181860632, ExAC 0.02%). This variant has been reported in the literature as biallelic with other missense POLG variants in several individuals affected with Alper's syndrome and chronic progressive external ophthalmoplegia (PMID: 18195149, 22189570. 19251978), and as heterozygous in an individual with complex I deficiency (PMID: 20818383). ClinVar contains an entry for this variant (Variation ID: 206548). This variant is located within a polymerase domain of POLG that is important for keeping the balance between pol and exo activity of this mitochondrial replicase. A structure-function molecular model developed specifically for the POLG gene suggests that this missense change may result in diminishing the fidelity of the polymerase intrinsic process and thus has been determinated to be deleterious (PMID: 21824913). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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, SCV000887120.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The NM_002693.2:c.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18195149 . This variant meets the following evidence codes reported in the ACMG-guideline. 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. 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 Likely Pathogenic.

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

Last Updated: Mar 30, 2019

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