NM_002693.2(POLG):c.1763G>A (p.Gly588Asp) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jan 10, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000413337.2

Allele description [Variation Report for NM_002693.2(POLG):c.1763G>A (p.Gly588Asp)]

NM_002693.2(POLG):c.1763G>A (p.Gly588Asp)

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.1763G>A (p.Gly588Asp)
HGVS:
  • NC_000015.10:g.89325636C>T
  • NG_008218.2:g.14160G>A
  • NM_001126131.2:c.1763G>A
  • NM_002693.2:c.1763G>A
  • NP_001119603.1:p.Gly588Asp
  • NP_002684.1:p.Gly588Asp
  • LRG_765t1:c.1763G>A
  • LRG_765:g.14160G>A
  • LRG_765p1:p.Gly588Asp
  • NC_000015.9:g.89868867C>T
Protein change:
G588D
Links:
dbSNP: rs371334941
NCBI 1000 Genomes Browser:
rs371334941
Molecular consequence:
  • NM_001126131.2:c.1763G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.1763G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000491091GeneDxcriteria provided, single submitter
Likely pathogenic
(Dec 29, 2015)
germlineclinical testing

Citation Link,

SCV000705195EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Uncertain significance
(Jan 10, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000491091.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The G588D variant in the POLG gene has been reported as a likely pathogenic variant in three unrelated individuals with clinical presentations suggestive of POLG deficiency who were each identified to harbor at least one known pathogenic POLG variant on the opposite allele (Tang et al., 2011). The G588D variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G588D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (P587L, P589L, L592F) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G588D variant is a strong candidate for a pathogenic variant.

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

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000705195.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Feb 27, 2021

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