NM_002693.2(POLG):c.32G>A AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Aug 25, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000633544.5

Allele description [Variation Report for NM_002693.2(POLG):c.32G>A]

NM_002693.3(POLG):c.32G>A (p.Gly11Asp)

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.32G>A (p.Gly11Asp)
HGVS:
  • NC_000015.10:g.89333723C>T
  • NG_008218.2:g.6073G>A
  • NM_001126131.2:c.32G>A
  • NM_002693.2:c.32G>A
  • NM_002693.3:c.32G>AMANE SELECT
  • NP_001119603.1:p.Gly11Asp
  • NP_002684.1:p.Gly11Asp
  • NP_002684.1:p.Gly11Asp
  • LRG_765t1:c.32G>A
  • LRG_765:g.6073G>A
  • LRG_765p1:p.Gly11Asp
  • NC_000015.9:g.89876954C>T
  • p.GLY11ASP
Protein change:
G11D
Links:
dbSNP: rs765472726
NCBI 1000 Genomes Browser:
rs765472726
Molecular consequence:
  • NM_001126131.2:c.32G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.32G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.32G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Progressive sclerosing poliodystrophy (MTDPS4A)
Synonyms:
Alpers disease; Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis; Alpers progressive infantile poliodystrophy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008758; MedGen: C0205710; Orphanet: 726; OMIM: 203700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000754790Invitaecriteria provided, single submitter
Uncertain significance
(Aug 25, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000886985Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicinecriteria provided, single submitter
Likely benign
(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

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

Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.

Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ.

J Med Genet. 2011 Oct;48(10):669-81. doi: 10.1136/jmedgenet-2011-100222. Epub 2011 Aug 31.

PubMed [citation]
PMID:
21880868
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000754790.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glycine with aspartic acid at codon 11 of the POLG protein (p.Gly11Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs765472726, ExAC 0.4%). This variant has been observed in several individuals affected with POLG-related disorders. However, in most cases it is reported on the same chromosome (cis) with another pathogenic variant (p.Arg852Cys) (PMID: 19251978, 18487244, 21880868, 22494076). ClinVar contains an entry for this variant (Variation ID: 195182). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their 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, SCV000886985.1

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

Description

The NM_002693.2:c.32G>A (NP_002684.1:p.Gly11Asp) [GRCH38: NC_000015.10:g.89333723C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18487244 . 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). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.

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

Last Updated: Nov 20, 2021

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