NM_002693.2(POLG):c.3151G>A (p.Gly1051Arg) 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:
RCV000685758.1

Allele description [Variation Report for NM_002693.2(POLG):c.3151G>A (p.Gly1051Arg)]

NM_002693.2(POLG):c.3151G>A (p.Gly1051Arg)

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.3151G>A (p.Gly1051Arg)
HGVS:
  • NC_000015.10:g.89319053C>T
  • NG_008218.2:g.20743G>A
  • NM_002693.2:c.3151G>A
  • NP_002684.1:p.Gly1051Arg
  • LRG_765t1:c.3151G>A
  • LRG_765:g.20743G>A
  • LRG_765p1:p.Gly1051Arg
  • NC_000015.9:g.89862284C>T
Protein change:
G1051R
Molecular consequence:
  • NM_002693.2:c.3151G>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
SCV000813255Invitaecriteria provided, single submitter
Uncertain significance
(Jun 5, 2018)
germlineclinical testing

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

SCV000887121Wong 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

Mitochondrial DNA defects in Saccharomyces cerevisiae caused by functional interactions between DNA polymerase gamma mutations associated with disease in human.

Baruffini E, Ferrero I, Foury F.

Biochim Biophys Acta. 2007 Dec;1772(11-12):1225-35. Epub 2007 Oct 14.

PubMed [citation]
PMID:
17980715

mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.

Stumpf JD, Bailey CM, Spell D, Stillwagon M, Anderson KS, Copeland WC.

Hum Mol Genet. 2010 Jun 1;19(11):2123-33. doi: 10.1093/hmg/ddq089. Epub 2010 Feb 25.

PubMed [citation]
PMID:
20185557
PMCID:
PMC2865372
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000813255.1

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

Description

This sequence change replaces glycine with arginine at codon 1051 of the POLG protein (p.Gly1051Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121918049, ExAC 0.001%). This variant has not been reported in the literature in individuals with a POLG-related disease. However, a different variant (c.3151G>C) giving rise to the same protein effect observed here (p.Gly1051Arg) has been reported biallelic with another pathogenic POLG variant (in trans) to segregate with autosomal recessive progressive external ophthalmoplegia in a family (PMID: 14745080). Experimental studies have shown that this missense change mildly impairs protein function (PMID: 17980715, 20185557). 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, SCV000887121.1

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

Description

The NM_002693.2:c.3151G>A (NP_002684.1:p.Gly1051Arg) [GRCH38: NC_000015.10:g.89319053C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:14745080 . 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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