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NM_002693.2(POLG):c.1276G>A (p.Gly426Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Aug 3, 2021)
Last evaluated:
Jun 13, 2020
Accession:
VCV000458687.4
Variation ID:
458687
Description:
single nucleotide variant
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NM_002693.2(POLG):c.1276G>A (p.Gly426Ser)

Allele ID
465378
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q26.1
Genomic location
15: 89327324 (GRCh38) GRCh38 UCSC
15: 89870555 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_765:g.12472G>A
NC_000015.10:g.89327324C>T
NC_000015.9:g.89870555C>T
... more HGVS
Protein change
G426S
Other names
-
Canonical SPDI
NC_000015.10:89327323:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Links
ClinGen: CA7724884
dbSNP: rs775576189
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Oct 31, 2018 RCV000763997.1
Likely pathogenic 1 criteria provided, single submitter Dec 16, 2019 RCV001546202.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Jun 13, 2020 RCV000534104.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
POLG - - GRCh38
GRCh37
1276 1392

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Oct 01, 2018)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000887142.1
Submitted: (Nov 16, 2018)
Evidence details
Comment:
The NM_002693.2:c.1276G>A (NP_002684.1:p.Gly426Ser) [GRCH38: NC_000015.10:g.89327324C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets … (more)
Uncertain significance
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1
Progressive sclerosing poliodystrophy
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Mitochondrial DNA depletion syndrome 1 (MNGIE type)
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Mitochondrial DNA depletion syndrome 4B, MNGIE type
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894948.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Uncertain significance
(Jun 13, 2020)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Invitae
Accession: SCV000630090.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces glycine with serine at codon 426 of the POLG protein (p.Gly426Ser). The glycine residue is highly conserved and there is a … (more)
Likely pathogenic
(Dec 16, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001765681.1
Submitted: (Aug 03, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. Tang S Journal of medical genetics 2011 PMID: 21880868
The unfolding clinical spectrum of POLG mutations. Blok MJ Journal of medical genetics 2009 PMID: 19578034

Text-mined citations for rs775576189...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 06, 2021