NM_002693.2(POLG):c.264C>G (p.Phe88Leu) AND Progressive sclerosing poliodystrophy

Clinical significance:Uncertain significance (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:
RCV000693072.1

Allele description [Variation Report for NM_002693.2(POLG):c.264C>G (p.Phe88Leu)]

NM_002693.2(POLG):c.264C>G (p.Phe88Leu)

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.264C>G (p.Phe88Leu)
HGVS:
  • NC_000015.10:g.89333491G>C
  • NG_008218.2:g.6305C>G
  • NM_002693.2:c.264C>G
  • NP_002684.1:p.Phe88Leu
  • LRG_765t1:c.264C>G
  • LRG_765:g.6305C>G
  • LRG_765p1:p.Phe88Leu
  • NC_000015.9:g.89876722G>C
Protein change:
F88L
Links:
dbSNP: rs144439703
NCBI 1000 Genomes Browser:
rs144439703
Molecular consequence:
  • NM_002693.2:c.264C>G - 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
SCV000820926Invitaecriteria provided, single submitter
Uncertain significance
(May 12, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000887296Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Uncertain significance
(Oct 1, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

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

A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity.

Tchikviladzé M, Gilleron M, Maisonobe T, Galanaud D, Laforêt P, Durr A, Eymard B, Mochel F, Ogier H, Béhin A, Stojkovic T, Degos B, Gourfinkel-An I, Sedel F, Anheim M, Elbaz A, Viala K, Vidailhet M, Brice A, Jardel C, Lombès A.

J Neurol Neurosurg Psychiatry. 2015 Jun;86(6):646-54. doi: 10.1136/jnnp-2013-306799. Epub 2014 Aug 11.

PubMed [citation]
PMID:
25118206
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000820926.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces phenylalanine with leucine at codon 88 of the POLG protein (p.Phe88Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs144439703, ExAC 0.02%). This variant has been observed in individuals affected with POLG-related disease (PMID: 25118206) and has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual with reduced mtDNA copy number in blood but with unknown clinical indication (PMID: 21880868, Invitae). 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: 381522). 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: "Benign"; Align-GVGD: "Class C0"). 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, SCV000887296.1

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

Description

The NM_002693.2:c.264C>G (NP_002684.1:p.Phe88Leu) [GRCH38: NC_000015.10:g.89333491G>C] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.

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

Last Updated: Apr 17, 2019

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