NM_002693.2(POLG):c.2207A>G (p.Asn736Ser) AND Progressive sclerosing poliodystrophy

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Oct 1, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000231376.4

Allele description [Variation Report for NM_002693.2(POLG):c.2207A>G (p.Asn736Ser)]

NM_002693.2(POLG):c.2207A>G (p.Asn736Ser)

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.2207A>G (p.Asn736Ser)
Other names:
p.N736S:AAT>AGT
HGVS:
  • NC_000015.10:g.89323462T>C
  • NG_008218.2:g.16334A>G
  • NM_002693.2:c.2207A>G
  • NP_002684.1:p.Asn736Ser
  • LRG_765t1:c.2207A>G
  • LRG_765:g.16334A>G
  • LRG_765p1:p.Asn736Ser
  • NC_000015.9:g.89866693T>C
Protein change:
N736S
Links:
dbSNP: rs138457939
NCBI 1000 Genomes Browser:
rs138457939
Molecular consequence:
  • NM_002693.2:c.2207A>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
SCV000287667Invitaecriteria provided, single submitter
Uncertain significance
(May 29, 2018)
germlineclinical testing

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

SCV000887295Wong Mito Lab, Molecular and Human Genetics,Baylor College of Medicinecriteria provided, single submitter
Benign
(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

Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation?

Verhoeven WM, Egger JI, Kremer BP, de Pont BJ, Marcelis CL.

Neuropsychiatr Dis Treat. 2011;7:293-6. doi: 10.2147/NDT.S20153. Epub 2011 May 15.

PubMed [citation]
PMID:
21654874
PMCID:
PMC3101889

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 (4)

Details of each submission

From Invitae, SCV000287667.4

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

Description

This sequence change replaces asparagine with serine at codon 736 of the POLG protein (p.Asn736Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs138457939, ExAC 0.1%). This variant has been reported as a variant of unknown significance in individuals affected with a spectrum of phenotypes suspected to be related to POLG-deficiency (PMID: 21654874, 21880868). ClinVar contains an entry for this variant (Variation ID: 206516). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, SCV000887295.1

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

Description

The NM_002693.2:c.2207A>G (NP_002684.1:p.Asn736Ser) [GRCH38: NC_000015.10:g.89323462T>C] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). 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). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.

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

Last Updated: Mar 30, 2019

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