NM_002693.2(POLG):c.2554C>T AND Progressive sclerosing poliodystrophy

Clinical significance:Pathogenic (Last evaluated: Oct 1, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000633537.2

Allele description [Variation Report for NM_002693.2(POLG):c.2554C>T]

NM_002693.2(POLG):c.2554C>T (p.Arg852Cys)

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.2554C>T (p.Arg852Cys)
Other names:
p.R852C:CGC>TGC
HGVS:
  • NC_000015.10:g.89321780G>A
  • NG_008218.2:g.18016C>T
  • NM_002693.2:c.2554C>T
  • NP_002684.1:p.Arg852Cys
  • LRG_765t1:c.2554C>T
  • LRG_765:g.18016C>T
  • LRG_765p1:p.Arg852Cys
  • NC_000015.9:g.89865011G>A
Protein change:
R852C
Links:
dbSNP: rs144500145
NCBI 1000 Genomes Browser:
rs144500145
Molecular consequence:
  • NM_002693.2:c.2554C>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
SCV000754783Invitaecriteria provided, single submitter
Pathogenic
(May 19, 2018)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000886909Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
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

Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.

Ashley N, O'Rourke A, Smith C, Adams S, Gowda V, Zeviani M, Brown GK, Fratter C, Poulton J.

Hum Mol Genet. 2008 Aug 15;17(16):2496-506. doi: 10.1093/hmg/ddn150. Epub 2008 May 16. Erratum in: Hum Mol Genet. 2009 Dec 15;18(24):4905-6.

PubMed [citation]
PMID:
18487244
PMCID:
PMC2486441

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.

Hakonen AH, Davidzon G, Salemi R, Bindoff LA, Van Goethem G, Dimauro S, Thorburn DR, Suomalainen A.

Eur J Hum Genet. 2007 Jul;15(7):779-83. Epub 2007 Apr 11.

PubMed [citation]
PMID:
17426723
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000754783.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This sequence change replaces arginine with cysteine at codon 852 of the POLG protein (p.Arg852Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs144500145, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Alpers syndrome (PMID:21880868, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In addition, this variant in combination with another POLG variant has been reported in individuals affected with Alpers syndrome (PMID: 16545482, 22000311), ataxia neuropathy spectrum (PMID: 18546365), Complex IV deficiency (PMID: 20818383, 22494076), and other POLG-related conditions (PMID: 17426723, 18487244). ClinVar contains an entry for this variant (Variation ID: 206528). Experimental studies have shown that this missense change abolishes polymerase activity (PMID: 19478085). For these reasons, this variant has been classified as Pathogenic.

#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, SCV000886909.1

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

Description

The NM_002693.2:c.2554C>T (NP_002684.1:p.Arg852Cys) [GRCH38: NC_000015.10:g.89321780G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16545482 . 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. PS3:Well established functional studies show a deleterious effect on POLG. 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. 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: Apr 17, 2019

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