NM_002693.2(POLG):c.1491G>C (p.Gln497His) 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:
RCV000528996.2

Allele description [Variation Report for NM_002693.2(POLG):c.1491G>C (p.Gln497His)]

NM_002693.2(POLG):c.1491G>C (p.Gln497His)

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.1491G>C (p.Gln497His)
Other names:
p.Q497H:CAG>CAC
HGVS:
  • NC_000015.10:g.89327006C>G
  • NG_008218.2:g.12790G>C
  • NM_001126131.1:c.1491G>C
  • NM_002693.2:c.1491G>C
  • NP_001119603.1:p.Gln497His
  • NP_002684.1:p.Gln497His
  • LRG_765t1:c.1491G>C
  • LRG_765:g.12790G>C
  • LRG_765p1:p.Gln497His
  • NC_000015.9:g.89870237C>G
  • NG_008218.1:g.12790G>C
  • P54098:p.Gln497His
Protein change:
Q497H; GLN497HIS
Links:
UniProtKB: P54098#VAR_023669; OMIM: 174763.0016; dbSNP: rs121918052
NCBI 1000 Genomes Browser:
rs121918052
Molecular consequence:
  • NM_002693.2:c.1491G>C - 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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000630098Invitaecriteria provided, single submitter
Uncertain significance
(Sep 12, 2017)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000886903Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Uncertain significance
(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

POLG1 manifestations in childhood.

Isohanni P, Hakonen AH, Euro L, Paetau I, Linnankivi T, Liukkonen E, Wallden T, Luostarinen L, Valanne L, Paetau A, Uusimaa J, Lönnqvist T, Suomalainen A, Pihko H.

Neurology. 2011 Mar 1;76(9):811-5. doi: 10.1212/WNL.0b013e31820e7b25.

PubMed [citation]
PMID:
21357833

Rapidly progressive neurological deterioration in a child with Alpers syndrome exhibiting a previously unremarkable brain MRI.

Brunetti-Pierri N, Selby K, O'Sullivan M, Hendson G, Truong C, Waters PJ, Wong LJ.

Neuropediatrics. 2008 Jun;39(3):179-83. doi: 10.1055/s-0028-1093334. Epub 2008 Nov 7.

PubMed [citation]
PMID:
18991199
See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000630098.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces glutamine with histidine at codon 497 of the POLG protein (p.Gln497His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs121918052, ExAC 0.04%). This variant has been reported in families and individuals affected with POLG-related conditions (PMID: 15824347, 25025039, 21357833, 18991199, 18546365, 25065347, 26942291). However, this variant commonly occurs on the same chromosome (in cis) with p.Trp748Ser and/or p.Glu1143Gly, so it is unclear if this particular variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 13510, 157526). 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"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. 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, SCV000886903.1

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

Description

The NM_002693.2:c.1491G>C (NP_002684.1:p.Gln497His) [GRCH38: NC_000015.10:g.89327006C>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:1582434 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Uncertain Significance.

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

Last Updated: Mar 30, 2019

Support Center