NM_002693.2(POLG):c.1157G>A (p.Arg386His) AND Progressive sclerosing poliodystrophy

Clinical significance:Uncertain significance (Last evaluated: Jan 22, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000633557.2

Allele description [Variation Report for NM_002693.2(POLG):c.1157G>A (p.Arg386His)]

NM_002693.2(POLG):c.1157G>A (p.Arg386His)

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.1157G>A (p.Arg386His)
HGVS:
  • NC_000015.10:g.89328698C>T
  • NG_008218.2:g.11098G>A
  • NM_002693.2:c.1157G>A
  • NP_002684.1:p.Arg386His
  • LRG_765t1:c.1157G>A
  • LRG_765:g.11098G>A
  • LRG_765p1:p.Arg386His
  • NC_000015.9:g.89871929C>T
Protein change:
R386H
Links:
dbSNP: rs1394411503
NCBI 1000 Genomes Browser:
rs1394411503
Molecular consequence:
  • NM_002693.2:c.1157G>A - 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
SCV000754803Invitaecriteria provided, single submitter
Uncertain significance
(Jan 22, 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

Predicting the contribution of novel POLG mutations to human disease through analysis in yeast model.

Baruffini E, Horvath R, Dallabona C, Czermin B, Lamantea E, Bindoff L, Invernizzi F, Ferrero I, Zeviani M, Lodi T.

Mitochondrion. 2011 Jan;11(1):182-90. doi: 10.1016/j.mito.2010.09.007. Epub 2010 Sep 29.

PubMed [citation]
PMID:
20883824

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000754803.2

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

Description

This sequence change replaces arginine with histidine at codon 386 of the POLG protein (p.Arg386His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant has been reported in the literature in an individual affected with suspected Alpers syndrome (PMID: 20883824). However, in that individual, only one allele was identified in the POLG gene. This variant is not present in population databases (ExAC no frequency). Experimental studies have shown that this missense change disrupts protein function, but is very mild with no mtDNA loss in yeast (PMID: 20883824). 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

Last Updated: Mar 30, 2019

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