NM_002693.2(POLG):c.679C>T (p.Arg227Trp) 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:
RCV000525480.2

Allele description [Variation Report for NM_002693.2(POLG):c.679C>T (p.Arg227Trp)]

NM_002693.2(POLG):c.679C>T (p.Arg227Trp)

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.679C>T (p.Arg227Trp)
HGVS:
  • NC_000015.10:g.89330257G>A
  • NG_008218.2:g.9539C>T
  • NM_002693.2:c.679C>T
  • NP_002684.1:p.Arg227Trp
  • LRG_765t1:c.679C>T
  • LRG_765:g.9539C>T
  • LRG_765p1:p.Arg227Trp
  • NC_000015.9:g.89873488G>A
  • NG_008218.1:g.9539C>T
  • P54098:p.Arg227Trp
Protein change:
R227W; ARG227TRP
Links:
UniProtKB: P54098#VAR_023663; OMIM: 174763.0021; dbSNP: rs121918056
NCBI 1000 Genomes Browser:
rs121918056
Molecular consequence:
  • NM_002693.2:c.679C>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
SCV000630161Invitaecriteria provided, single submitter
Pathogenic
(Jun 21, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000886918Wong 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

Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing.

Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, Dimauro S, Thorburn DR, Mootha VK.

Sci Transl Med. 2012 Jan 25;4(118):118ra10. doi: 10.1126/scitranslmed.3003310.

PubMed [citation]
PMID:
22277967
PMCID:
PMC3523805

Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations.

Giordano C, Powell H, Leopizzi M, De Curtis M, Travaglini C, Sebastiani M, Gallo P, Taylor RW, d'Amati G.

Neurology. 2009 Mar 24;72(12):1103-5. doi: 10.1212/01.wnl.0000345002.47396.e1. No abstract available. Erratum in: Neurology. 2009 Sep 1;73(9):738. de Curtis, M [corrected to De Curtis, M].

PubMed [citation]
PMID:
19307547
PMCID:
PMC2821839
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000630161.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with tryptophan at codon 227 of the POLG protein (p.Arg227Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs121918056, ExAC no frequency). This variant has been reported as compound heterozygous in several individuals affected with POLG-related disorders (PMID: 12707443, 22277967, 25281868, 16621917, 19307547, 16957900). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Alpers-Huttenlocher syndrome (PMID: 19307547). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 13515). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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, SCV000886918.1

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

Description

The NM_002693.2:c.679C>T (NP_002684.1:p.Arg227Trp) [GRCH38: NC_000015.10:g.89330257G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 . 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. 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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