NM_002693.2(POLG):c.1174C>G (p.Leu392Val) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Apr 10, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000188651.6

Allele description [Variation Report for NM_002693.2(POLG):c.1174C>G (p.Leu392Val)]

NM_002693.2(POLG):c.1174C>G (p.Leu392Val)

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.1174C>G (p.Leu392Val)
Other names:
p.L392V:CTG>GTG
HGVS:
  • NC_000015.10:g.89328532G>C
  • NG_008218.2:g.11264C>G
  • NM_002693.2:c.1174C>G
  • NP_002684.1:p.Leu392Val
  • LRG_765t1:c.1174C>G
  • LRG_765:g.11264C>G
  • LRG_765p1:p.Leu392Val
  • NC_000015.9:g.89871763G>C
Protein change:
L392V
Links:
dbSNP: rs145289229
NCBI 1000 Genomes Browser:
rs145289229
Molecular consequence:
  • NM_002693.2:c.1174C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
8

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000231656EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Likely benign
(Apr 10, 2018)
germlineclinical testing

Citation Link,

SCV000242274GeneDxcriteria provided, single submitter
Uncertain significance
(Mar 20, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown8not providednot providednot providednot providedclinical testing

Details of each submission

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000231656.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided8not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided8not providednot providednot provided

From GeneDx, SCV000242274.12

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

Description

A variant of uncertain significance has been identified in the POLG gene. The L392V missense change was previously identified in cis with another POLG variant in an individual with Parkinson disease and in several unaffected control individuals (Luoma et al., 2007). L392V was subsequently reported on the same allele (in cis) with an in-frame duplication (c.3240_3242dupCCG reported as p.R1081dup) in an individual with Alpers disease who had another POLG pathogenic variant on the other allele (Cardenas et al., 2010). L392V has also been identified in multiple individuals with clinical features of a POLG disorder who did not have a second identifiable pathogenic variant, suggesting it may be a benign variant (Wong et al., 2008; Tang et al., 2011). The L392V variant is observed in 48/6576 (0.7%) alleles from individuals of Finnish background, including a homozygous individual, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution alters a position that is highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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

Last Updated: Mar 30, 2019

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