NM_002693.2(POLG):c.1A>G (p.Met1Val) AND Progressive sclerosing poliodystrophy

Clinical significance:Uncertain significance (Last evaluated: Dec 18, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000633552.1

Allele description [Variation Report for NM_002693.2(POLG):c.1A>G (p.Met1Val)]

NM_002693.2(POLG):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)
HGVS:
  • NC_000015.10:g.89333754T>C
  • NG_008218.2:g.6042A>G
  • NM_002693.2:c.1A>G
  • NP_002684.1:p.Met1Val
  • LRG_765t1:c.1A>G
  • LRG_765:g.6042A>G
  • LRG_765p1:p.Met1Val
  • NC_000015.9:g.89876985T>C
Protein change:
M1V
Links:
dbSNP: rs201786897
NCBI 1000 Genomes Browser:
rs201786897
Molecular consequence:
  • NM_002693.2:c.1A>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
SCV000754798Invitaecriteria provided, single submitter
Uncertain significance
(Dec 18, 2017)
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

Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma.

Ropp PA, Copeland WC.

Genomics. 1996 Sep 15;36(3):449-58.

PubMed [citation]
PMID:
8884268

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, SCV000754798.1

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

Description

This sequence change affects the initiator methionine of the POLG mRNA. The next in-frame methionine is located in exon 2 (p.Met78) and could potentially rescue the loss of initiator codon. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with POLG-related disease. Experimental studies have not been reported for this initiatior codon variant and it is currently unknown if translation is rescued by either an in-frame or out-of-frame methionine. If translation is rescued, the resulting POLG protein would lack the N-terminal mitochondrial targeting sequences (amino acids 1-25), which facilitates the normal subcellular localization of protein in the mitochondria (PMID: 8884268). 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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